Conditions: Platinum-resistant Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Cancer
Keywords: PROC EOC ALKS 4230 IL-2 Ovarian Cancer KEYNOTE-C71 Platinum Resistant Epithelian Ovarian Cancer Nemvaleukin alfa Pembrolizumab ARTISTRY-7 ART-7 paclitaxel pegylated liposoma doxorubicin PLD topotecan gemzar gemcitabine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 456
Healthy volunteers: no

Brief summary:
This is a Phase 3, multicenter, open-label, randomized study of nemvaleukin in combination with pembrolizumab versus protocol-specific Investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Detailed description:
Patients will be centrally allocated in a randomized fashion (3:1:1:3) to receive either:

Arm 1: Nemvaleukin and pembrolizumab combination therapy Arm 2: Pembrolizumab monotherapy Arm 3: Nemvaleukin monotherapy Arm 4: Investigator's choice chemotherapy include one of the following: pegylated liposomal doxorubicin (PLD), paclitaxel, topotecan, or gemcitabine.

Arms:
arm 1: None arm 2: None arm 3: None arm 4: Options for protocol-specific Investigator's choice chemotherapy include one of the following: pegylated liposomal doxorubicin (PLD), paclitaxel, topotecan, or gemcitabine. The Investigator will pre-select the Investigator's choice treatment before the randomization of each patient.

Interventions: intervention 1: Nemvaleukin and Pembrolizumab Combination intervention 2: Pembrolizumab intervention 3: Nemvaleukin intervention 4: Pegylated Liposomal Doxorubicin (PLD) intervention 5: Paclitaxel intervention 6: Topotecan intervention 7: Gemcitabine
Intervention descriptions: intervention 1: Nemvaleukin: 6 µg/kg/day; Days 1 through 5 of 21-day cycles; IV infusion over 30 minutes and Pembrolizumab: 200 mg; Day 1 of 21-day cycles; IV infusion over 30 minutes intervention 2: Pembrolizumab: 200 mg; Day 1 of 21-day cycles; IV infusion over 30 minutes intervention 3: Nemvaleukin: 6 µg/kg/day; Days 1 through 5 of 21-day cycles; IV infusion over 30 minutes intervention 4: 40 mg/m2; Day 1 of 28-day cycles; IV infusion; 1 mg/min (Cycle 1); 60 min infusion (Cycles 2+) intervention 5: 80 mg/m2; Days 1, 8, 15, and 22 of 28-day cycles; IV infusion over 60 min intervention 6: 4 mg/m2; Days 1, 8, and 15 of 28-day cycles; or 1.25 mg/m2, Days 1 through 5 of 21-day cycles; IV infusion over 30 min intervention 7: 1,000 mg/m2; Days 1 and 8 of 21-day cycles; IV infusion over 30 min

Protocol document:
Prot_000.pdf: 
1. 
TITLE PAGE 
 
 
CLINICAL STUDY PROTOCOL 
ALKS 4230-007/GOG-3063/ENGOT-ov68/APGOT-OV8 
 
Eudra CT: 2021-002326-24 
 
Study title: 
A Phase 3, Multicenter, Open-Label, Randomized Study of Nemvaleukin 
Alfa in Combination With Pembrolizumab Versus Investigator’s Choice 
Chemotherapy in Patients With Platinum-Resistant Epithelial Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer (ARTISTRY-7) 
Document/Date: 
Version 5.0 
Version 4.0 
Version 3.0 
Version 2.0 
Version 1.0  
31 Jan 2024 
14 Aug 2023 
05 Oct 2022 
05 Oct 2021 
19 Aug 2021 
Sponsor: 
Mural Oncology, Inc. (referred to herein as “Mural”) 
852 Winter Street 
Waltham, MA 02451 
USA 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, 
which is the property of Mural Oncology, Inc. No person is authorized to make it public without the 
written permission of Mural Oncology, Inc. These restrictions or disclosures will apply equally to all 
future information supplied to you that is indicated as privileged or confidential. 


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Protocol ALKS 4230-007 Version 5.0 
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2 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Study Lead and 
Medical Monitor  
Rita Dalal, 
MBBS, MPH  
Mural Oncology, Inc. 
852 Winter Street 
Waltham, MA 02451-1420 
US 
Phone Number: +1 (781) 614-0097 
Email: rita.dalal@muraloncology.com 
ARTISTRY-7_Medical_Monitoring@muraloncology.com 
SAE and Pregnancy 
Reporting 
PPD 
PPD 
Toll Free Fax: +1 (888) 488-9697 
Direct Dial Fax: +1 (919) 654-3849 
Email: WILSafety@ppd.com 
SAE=serious adverse event, US=United States 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: Mural Oncology, Inc. 
Name of Investigational Product: nemvaleukin alfa 
Title of Study: A Phase 3, Multicenter, Open-Label, Randomized Study of Nemvaleukin Alfa in 
Combination With Pembrolizumab Versus Investigator’s Choice Chemotherapy in Patients With 
Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARTISTRY-7) 
Study Center: A multicenter study conducted globally 
Planned Study Period: Third quarter (Q3) 2021 to Q1 2025 
Phase of Development: 3 
Study Objectives 
Study Endpoints 
Primary Objective: 
• 
To evaluate the overall survival (OS) of 
nemvaleukin in combination with 
pembrolizumab as compared with 
chemotherapy in patients with platinum 
resistant ovarian cancer 
Primary Endpoint: 
• 
OS 
Secondary Objectives: 
• 
To evaluate the antitumor activity of 
nemvaleukin in combination with 
pembrolizumab as compared with 
chemotherapy 
• 
To evaluate the safety of nemvaleukin in 
combination with pembrolizumab as 
compared with chemotherapy 
Secondary Endpoints: 
• 
Progression-free survival (PFS) as assessed by 
Investigator, based on Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 
• 
Objective response rate (ORR) as assessed by 
Investigator, based on RECIST v1.1 
• 
Disease control rate (DCR), duration of 
response (DOR), and time to response (TTR) as 
assessed by Investigator, based on RECIST v1.1 
• 
Cancer antigen (CA)-125 response as defined by 
the Gynecologic Cancer InterGroup (GCIG) 
• 
Safety as assessed by treatment-emergent 
adverse events (TEAEs), clinical laboratory 
parameters, vital signs, and electrocardiograms 
(ECGs) 
Exploratory Objectives: 
• 
To evaluate the antitumor activity of 
pembrolizumab monotherapy; to evaluate 
the antitumor activity of nemvaleukin 
monotherapy 
• 
To evaluate health-related quality of life 
(HRQoL) 
Exploratory Endpoints: 
• 
PFS, ORR, DOR, TTR, and OS of the 
monotherapy arms as assessed by Investigator, 
based on RECIST v1.1 
• 
HRQoL as assessed by the following 
patient-reported outcome instruments: the 
Functional Assessment of Cancer Therapy – 
Ovarian (FACT-O) questionnaire and the 
EuroQol 5 Dimension 5-Level (EQ-5D-5L) 
questionnaire 


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• 
To determine if any baseline or changes 
in parameters in tumor tissue and/or 
peripheral blood may correlate to 
response to treatment with nemvaleukin 
in combination with pembrolizumab 
• 
To evaluate the pharmacokinetics (PK), 
immunogenicity, and pharmacodynamic 
effects of nemvaleukin and/or 
pembrolizumab in this treatment regimen 
• 
Pretreatment levels, on-treatment levels, and/or 
changes from pretreatment levels of the 
following parameters (in tumor specimens and/or 
peripheral blood): 
− 
Combined positive score (CPS) of 
programmed death ligand-1 (PD-L1), tumor 
mutational burden (TMB), and other relevant 
genetic and non-genetic predictive markers 
(eg, homologous recombination deficiency, 
breast cancer gene [BRCA] mutation) 
− 
Serum concentrations of nemvaleukin (and 
pembrolizumab as appropriate) 
− 
Presence of anti-nemvaleukin antibodies 
(and anti-pembrolizumab antibodies as 
appropriate) in serum 
− 
Leukocytes including, but not limited to, 
circulating cluster of differentiation (CD)8+ 
T cells, regulatory T cells, and natural killer 
(NK) cells 
− 
Serum concentrations of interferon-γ, 
interleukin (IL)-6, and other soluble proteins 
Methodology: This is a Phase 3, multicenter, open-label, randomized study of nemvaleukin in 
combination with pembrolizumab versus protocol-specific Investigator’s choice chemotherapy in 
patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. 
All patients will attend a Screening Visit, at which informed consent will be obtained, eligibility will 
be assessed, and demographics, medical history, prior and concomitant medications, and prior 
procedures will be reviewed and recorded. If tumor tissue is to be collected for central testing of 
PD-L1 status prior to Screening, a pre-screening informed consent form will be obtained. For the 
purposes of confirming the diagnosis of epithelial ovarian cancer (EOC) and for evaluating 
pretreatment tumor expression of genes and/or proteins of interest (eg, PD-L1 status, TMB, and 
microsatellite instability), an initial tumor biopsy will be obtained prior to the start of treatment, if 
such tissue is not already available. Archival tissue can be used in place of pretreatment biopsy. 
PD-L1 status via central vendor will be required prior to randomization. 
Per the original study design, patients were centrally allocated in a randomized fashion (3:1:1:3) to 
receive either: 
• 
Arm 1: nemvaleukin and pembrolizumab combination therapy 
• 
Arm 2: pembrolizumab monotherapy (closed) 
• 
Arm 3: nemvaleukin monotherapy (closed) 
• 
Arm 4: Investigator’s choice chemotherapy. Options for protocol-specific Investigator’s 
choice chemotherapy include one of the following: pegylated liposomal doxorubicin 
(PLD), paclitaxel, topotecan, or gemcitabine. The Investigator will pre-select the 
Investigator’s choice treatment before the randomization of each patient. 


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The pembrolizumab monotherapy arm (Arm 2) met its pre-specified futility criteria at the planned 
futility analysis and was closed to enrollment as of 31 Aug 2023, per the recommendation of the 
Independent Data Monitoring Committee (IDMC). The nemvaleukin monotherapy arm (Arm 3) did 
not meet its pre-specified futility criteria at the planned futility analysis and the IDMC recommended 
continuation. Under protocol version 4.0, the nemvaleukin monotherapy arm (Arm 3) reached its 
intended enrollment and thus closed. Because no changes have been made to the objectives related to 
Arm 3 in protocol version 5.0, the Arm 3 number of patients was not recalculated. Therefore, in 
protocol version 5.0, eligible patients will continue to be enrolled in the remaining 2 arms and will be 
centrally allocated with a randomization ratio of 1:1 to the Combination and Chemotherapy arms 
(Arm 1 and Arm 4, respectively). 
To ensure equal distribution of prognostic factors in the study arms, patients will be stratified 
according to the following parameters: 
• 
PD-L1 status (immunohistochemistry CPS ≥10 vs CPS <10) 
• 
Histological subtype (high-grade serous vs non-high-grade serous) 
• 
Investigator’s choice chemotherapy (paclitaxel vs other chemotherapies) 
Response assessments will include computed tomography (CT) scans and/or magnetic resonance 
imaging (MRI) every 6 weeks (Year 1) and every 12 weeks (q12w) (Year 2+), with mandatory 
relevant imaging of chest, abdomen, and/or pelvis. Brain imaging at baseline (and during the study) 
should be performed when there is a history/suspicion of brain metastasis. Response and PFS will be 
evaluated per RECIST v1.1 guidelines. For patients who complete treatment or discontinue treatment 
for reasons other than disease progression, every effort should be made to continue monitoring their 
disease status by radiologic imaging q6w (Year 1 from start of treatment) or q12w (Years 2+ from 
start of treatment) starting from the last on-treatment assessment until (1) the assessment of 
progressive disease (PD), (2) the initiation of new anticancer therapy(ies), (3) withdrawal of consent, 
(4) death, or (5) end of study, whichever occurs first. 
Study Design Schematic 
 
EOT=end of treatment, IV=intravenous, PLD=pegylated liposomal doxorubicin. 
Note: As of protocol version 5.0, the pembrolizumab and nemvaleukin monotherapy arms (Arm 2 and Arm 3, 
respectively) are closed to enrollment. 
* Treatment with pembrolizumab (Arms 1 and 2) is allowed for up to a maximum of 35 cycles (approximately 
2 years). 
**Alternatively, topotecan may be administered at 1.25 mg/m2 on Days 1 through 5 of 21-day cycles. 


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Number of Patients (Planned): Approximately 376 patients were originally planned in a 3:1:1:3 
ratio across 4 arms: 141 patients in Arm 1 (combination therapy), 47 patients in Arm 2 
(pembrolizumab monotherapy), 47 patients in Arm 3 (nemvaleukin monotherapy), and 141 patients in 
Arm 4 (Investigator’s choice chemotherapy). Under protocol version 5.0, approximately 450 patients 
are planned, including approximately 366 patients planned across Arm 1 and Arm 4 (approximately 
183 patients in each arm). Under protocol version 5.0, no additional patients will be enrolled in the 
pembrolizumab monotherapy or nemvaleukin monotherapy arms (Arm 2 and Arm 3, respectively). 
Inclusion Criteria: In order to qualify for participation in the study, patients must meet all of the 
following criteria and, when applicable (per schedule of assessments) the assessment should occur 
within 10 days prior to expected Cycle 1 Day 1 (C1D1) (closer to C1D1 is highly recommended): 
1. Patient is female and ≥18 years of age. 
2. Patient or patient’s legal representative (as applicable per regional requirements) has provided 
written informed consent. 
3. Patient is willing and able to comply with scheduled visits, treatment schedule, laboratory 
tests, and other requirements of the study. 
4. Patient has histologically confirmed diagnosis of EOC, fallopian tube cancer, or primary 
peritoneal cancer and histology subtype: high-grade serous, endometrioid of any grade, clear 
cell. 
5. Patient has platinum-resistant/refractory disease: resistant is defined as disease progression 
within 180 days following the last administered dose of platinum therapy beyond first-line 
setting (ie, initial platinum therapy); and refractory is defined as disease progression or lack of 
response followed by disease progression while receiving the most recent platinum-based 
therapy (ie, beyond initial therapy). Patient must have progressed radiographically or by 
GCIG-defined CA-125 criteria on or after their most recent line of anticancer therapy beyond 
first-line setting. 
a. Note: Progression should be calculated from the date of the last administered dose of 
platinum therapy to the date of the radiographic imaging showing progression or the date 
progression was assessed by GCIG-defined CA-125 criteria, whichever comes first. 
b. Note: Patients who have primary platinum-refractory or platinum-resistant disease 
(disease progression <3 months after completion of first-line platinum-based therapy) are 
excluded (see Exclusion Criterion 1). 
6. Patient must have received at least 1 prior line of platinum-based therapy (as noted below) 
and no more than 5 prior lines of systemic anticancer therapy in platinum-resistant disease 
(4 additional lines after the patient developed platinum-resistant/refractory disease). Patient 
must have received at least 1 line of therapy containing bevacizumab. The following 
guidelines apply: 
a. Patients who are primary platinum resistant (developed resistance after initial 
platinum-based therapy) must have received at least 4 cycles of platinum, must have had a 
response (complete response [CR] or partial response [PR]) and then progressed ≥3 to 
≤6 months after the date of the last dose of platinum. 
b. Prior poly adenosine diphosphate-ribose polymerase (PARP) inhibitor is allowed if 
included within these limits of prior therapy. Prior PARP inhibitor is required for patients 
with a BRCA mutation. 
c. Adjuvant ± neoadjuvant is considered 1 line of therapy. 


Mural Oncology, Inc. 
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d. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered part of the 
preceding line of therapy (ie, not counted independently). 
e. Therapy that changed due to toxicity in the absence of progression will be considered part 
of the same line (ie, not counted independently). 
f. Hormonal therapy will be counted as a separate line of therapy unless it was given as 
maintenance therapy. 
7. Patient has at least one measurable lesion that qualifies as a target lesion based on 
RECIST v1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 
8. Patient is willing to provide a tumor tissue sample either collected from a prior biopsy or 
cytoreductive/debulking surgery occurring at any time since diagnosis or from a fresh biopsy 
(newly obtained tumor tissue) at Screening. A tumor tissue sample collected at Screening 
(fresh biopsy) is preferred. Collection of tumor tissue samples from both prior biopsy or 
cytoreductive/debulking surgery and fresh biopsy are recommended (when possible) to 
understand changes in the tumor microenvironment during treatment. Central testing of 
PD-L1 status will be required prior to randomization. 
9. Patient has recovered from the effects of any previous chemotherapy, immunotherapy, other 
prior systemic anticancer therapy, radiotherapy, and/or surgery (ie, residual toxicity no worse 
than Grade 1 [Grade 2 treatment-associated peripheral neuropathy and/or any grade of 
alopecia are acceptable assuming all other inclusion criteria are met]). 
10. Patient who has received prior systemic anti-neoplastic agent(s) must wait at least 5 half-lives 
or 4 weeks (whichever is shorter) following prior therapy before enrollment into the study or 
4 weeks if the half-life of a given investigational agent is not known. 
11. Patient has an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and an estimated 
life expectancy of at least 3 months. 
12. Patient has adequate hematologic reserve, as evidenced by: 
a. Absolute neutrophil count of ≥1,500/µL; 
b. Absolute lymphocyte count of ≥500/µL; 
c. Platelet count of ≥100,000/µL; and 
d. Hemoglobin of ≥9 g/dL (patient may be transfused to this level if necessary, but 
transfusion must occur >1 week prior to the first dose of study drug[s] and hemoglobin 
maintained to an acceptable level [≥9 g/dL] prior to first dose). 
Note: Administration of granulocyte colony-stimulating factor (G-CSF) or erythropoietin 
stimulating factor is permitted according to approved indications and scientific 
recommendations. Administration of long-acting G-CSF must occur >2 weeks prior to the 
first dose of study drug(s). Administration of short-acting G-CSF must occur >1 week 
prior to the first dose of study drug(s). 
13. Patient has adequate hepatic function, as evidenced by aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) values ≤3 × the upper limit of normal (ULN) and serum total 
bilirubin values of ≤1.5 × ULN (≤2 × ULN for patients with known Gilbert’s syndrome). For 
patients with documented baseline liver metastasis, the following limits will apply: ≤5 × ULN 
for ALT/AST and ≤2 × ULN for bilirubin. 


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14. Patient has adequate renal function, as evidenced by a calculated creatinine clearance of 
≥45 mL/min by the Cockcroft-Gault equation or a serum creatinine ≤1.5 × ULN. Creatinine 
clearance assessed by the Cockcroft-Gault equation is preferred over serum creatinine when 
assessing patient eligibility. 
15. Patient has international normalized ratio (INR) and/or prothrombin time and activated partial 
thromboplastin time (aPTT) ≤1.5 × ULN unless the patient is receiving anticoagulant therapy, 
in which case INR and/or prothrombin time and aPTT must be within the desired therapeutic 
range of intended use for such anticoagulants. 
16. Patient agrees to abide by the contraceptive requirements detailed in the protocol 
(Appendix 1). 
17. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum or 
urine). (See Appendix 1 of the protocol for the definition of WOCBP.) 
Exclusion Criteria: In order to qualify for participation in the study, patients must not meet any of 
the following criteria and, when applicable (per schedule of assessments) the assessment should occur 
within 10 days prior to expected C1D1 (closer to C1D1 is highly recommended): 
1. Patient has primary platinum-refractory disease or primary platinum resistance: primary 
platinum-refractory disease is defined as disease progression during initial platinum-based 
therapy; and primary platinum resistance is defined as disease progression <3 months after 
completion of initial platinum-based therapy. 
2. Patient has histologically confirmed diagnosis of EOC with mucinous or carcinosarcoma 
subtype. 
3. Patient has nonepithelial tumor (eg, germline or stromal cell tumor) or ovarian tumor with 
low malignant potential (ie, borderline or low-grade serous tumor). 
4. Patient requires recurrent (≥1 per month) fluid drainage (eg, paracentesis, thoracentesis, 
pericardiocentesis) or patient requires fluid drainage of ≥500 mL within 4 weeks of the 
expected date of the first dose of study drug. 
5. Patient has received prior IL-2-based or IL-15-based cytokine therapy; patient has had 
exposure, including intralesional, to IL-12 or analogs thereof. 
6. Patient has prior exposure to any anti-programmed death receptor-1 (PD-1)/PD-L1 therapy. 
7. Patient requires or has taken systemic corticosteroids (>10 mg of prednisone daily, or 
equivalent) within 14 days prior to the first dose of study drug(s); however, replacement 
doses, topical, ophthalmologic, and inhalational steroids are permitted.  
Note: patients requiring the use of a steroid during the Screening Period at a dose level of 
<10 mg of prednisone (or equivalent) per day are not excluded as long as the event requiring 
the use of the steroid has recovered to acceptable grade. 
8. Patient has taken nonsteroid systemic immunomodulatory agents (eg, etanercept, 
adalimumab, etc) within 28 days prior to the first dose of study drug(s) or anticipates any use 
of these therapies during the study period.  


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9. Patient has undergone any major surgical procedure within 3 weeks prior to Screening. 
Patients who have not recovered from any previous surgery that occurred more than 3 weeks 
prior to Screening are also excluded. 
10. Patient has undergone prior solid organ and/or non-autologous hematopoietic stem cell or 
bone marrow transplant. 
11. Patient has received a live or live-attenuated vaccine(s) within 30 days prior to the first dose 
of study drug(s). Note: Coronavirus Disease 2019 (COVID-19) vaccine is allowed; see 
guidance on COVID-19 vaccines in the body of the protocol. 
12. Patient has had any active infection and/or a fever ≥38.5°C (≥101°F) within 7 days prior to 
the first dose of study drug(s) requiring systemic therapy. Antibiotics given for 
peri-procedural prophylaxis or given presumptively for a limited time (eg, until infection was 
ruled out), as well as topical or intraocular antibiotics, shall not be exclusionary. 
13. Patient has active autoimmune disease(s) requiring systemic treatment within the past 2 years 
or a documented history of clinically severe autoimmune disease that has required chronic or 
frequent systemic steroids. Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed. 
14. Patient has underlying chronic lung disease, chronic obstructive pulmonary disease, 
metastatic lung disease, pleural effusions, or other lung disorders (eg, pulmonary embolism) 
with a baseline room air oxygen saturation of <92% at Screening and/or dyspnea (≥Grade 3) 
which requires oxygen therapy. 
15. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis. 
16. Patient has any other concurrent uncontrolled illness or laboratory findings that may interfere 
with the planned treatment, affect patient compliance, such as recent serious trauma, or 
mental illness or substance use, which may interfere with the ability of the patient to 
cooperate and participate in the study. 
17. Patient is at high risk of treatment-related complications (see protocol for examples). 
18. Patient has had an active second malignancy within the previous 2 years. This criterion does 
not apply to patients with adequately treated basal cell or squamous cell skin cancer, 
carcinoma in situ of the cervix, urothelial carcinoma in situ, or ductal carcinoma in situ of the 
breast that has undergone full surgical resection. 
19. Patient is currently pregnant, breastfeeding, or is planning to become pregnant or to begin 
breastfeeding during the study period or within 120 days after last study drug administration. 
20. Patient has active or symptomatic central nervous system (CNS) metastases unless all the 
following have been met: such metastases have been treated by surgery and/or radiation 
therapy, and/or gamma knife and have remained radiographically stable (or shrinking) on 
2 consecutive imaging examinations performed at least 6 weeks apart; and steroids have been 
tapered to a dose of 10 mg of prednisone (or equivalent) or less for at least 2 weeks prior to 
first dose of study drug(s); and the patient is neurologically stable. Patients with history of 
brain metastases or a suspicion of brain metastases must have a brain MRI at baseline. 


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21. Patient has known or suspected hypersensitivity to pembrolizumab, nemvaleukin, PLD, 
paclitaxel, topotecan, gemcitabine, or to any of their excipients. 
Note: hypersensitivity to one or more of the chemotherapy choices is not exclusionary as long 
as the Investigator is able to select 1 of the 4 chemotherapy options for which the patient is 
known not to be hypersensitive. 
22. Patient has active uncontrolled coagulopathy. 
23. Patient has QT interval corrected by the Fridericia Correction Formula values of >470 msec; 
patient who is known to have congenital prolonged QT syndromes; or patient who is on 
medications known to cause prolonged QT interval on ECG. 
24. Patient is known to be positive for human immunodeficiency virus (HIV).  
• 
For sites in Czech Republic only: patients test positive for HIV at Screening. 
25. Patients with known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) are 
excluded; however, a patient with past hepatitis B virus (HBV) infection or resolved HBV 
infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) may be 
enrolled provided that HBV DNA is negative. Patients with known active hepatitis C 
(eg, hepatitis C virus [HCV] RNA [qualitative] are detected) are excluded; however, a patient 
with cured hepatitis C (negative HCV RNA status) may be enrolled.  
• 
For sites in Czech Republic only: patients test positive for HBV or HCV at Screening. 
26. History of bowel obstruction, history of abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within 3 months before the first dose of study drug is administered. 
Clinical symptoms of bowel obstruction should be ruled out by appropriate imaging studies 
during the Screening Period and prior to randomization in the study. Patients with a 
functioning ostomy can be included in the study. 
27. Patients who are investigational site staff members directly involved in the conduct of the 
study or their immediate family members as well as site staff members otherwise supervised 
by the Investigator, or patients who are employed by Mural or companies/vendors hired to be 
directly involved in the conduct of the study (immediate family is defined as a spouse, parent, 
child, or sibling, whether biological or legally adopted) unless the investigational site staff or 
staff at Mural or companies/vendors working on behalf of Mural are recusing themselves 
from the study activities. 
Investigational Product, Dosage, and Mode of Administration: Nemvaleukin drug product is 
supplied at a concentration of 1 mg/mL in a single-dose vial of lyophilized powder. Patients receiving 
nemvaleukin will be administered nemvaleukin at 6 µg/kg/day for 5 consecutive days, every 21 days 
(q21d), via a 30-minute intravenous (IV) infusion. 
Pembrolizumab is supplied as single-dose vials of either lyophilized powder or solution. Patients 
receiving pembrolizumab will be administered pembrolizumab at 200 mg q21d via a 30-minute IV 
infusion. 
For patients randomized to Arm 1, nemvaleukin will be administered prior to pembrolizumab.  


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Reference Therapy, Dosage, and Mode of Administration: Treatment of protocol-specific 
Investigator’s choice is to include any of the single-agent chemotherapies listed below, with the 
dosing schedule provided below. Chemotherapy agents will be sourced via institution and 
documented accordingly. Institutional guidelines can be followed for duration of infusion to avoid or 
manage the hypersensitivity reactions. Note: Single-agent chemotherapy must be selected prior to 
randomization. 
• 
PLD: 40 mg/m2; IV infusion of 1 mg/min (Cycle 1), 60-minute infusion (Cycles 2+); 
Day 1 of 28-day cycles 
• 
Paclitaxel: 80 mg/m2; IV infusion over 60 min; Days 1, 8, 15, and 22 of 28-day cycles 
• 
Topotecan: 4 mg/m2; IV infusion over 30 min; Days 1, 8, and 15 of 28-day cycles. 
Alternatively, 1.25 mg/m2; IV infusion over 30 min; Day 1 through 5 of 21-day cycles 
• 
Gemcitabine: 1,000 mg/m2; IV infusion over 30 min; Days 1 and 8 of 21-day cycles 
Duration of Treatment and Duration of Study: Duration of treatment depends on the arm in which 
the patient is enrolled. Patients will receive treatment with nemvaleukin for as long as they are 
experiencing disease control and are tolerating treatment well, or until any other criteria for treatment 
discontinuation are met. Patients who discontinue either nemvaleukin or pembrolizumab due to 
unacceptable toxicity that cannot be managed by dose modification must discontinue both study 
treatments. Patients who require treatment hold for either nemvaleukin or pembrolizumab due to 
unacceptable toxicity, based on recommendation in Table 9, may hold both study treatments. 
However, holding one agent is feasible if the Investigator’s causality assessment clearly attributes the 
adverse event (AE) to only one of the components. Treatment with pembrolizumab (Arms 1 and 2) 
will be allowed for up to a maximum of 35 treatments (35 cycles; approximately 2 years). Patients in 
the nemvaleukin and pembrolizumab combination therapy (Arm 1) may continue nemvaleukin as 
monotherapy without pembrolizumab beyond 35 cycles upon discussion with the Sponsor and not 
meeting any other criteria for discontinuation. 
Patients will receive chemotherapy for as long as they are experiencing disease control and are 
tolerating treatment well, or until any other criteria for treatment discontinuation are met. 
Patients will be followed for survival for up to 3 years after initiation of treatment or until closure of 
study, whichever comes first. 
Statistical Methods: In general, summary statistics (n, mean, standard deviation, median, minimum, 
and maximum values for continuous variables and number and percentage of patients in each category 
for categorical variables) will be provided for evaluated variables by treatment arms. Study drug is 
defined as nemvaleukin and/or pembrolizumab, or Investigator’s choice chemotherapy. 
All individual patient-level data will be presented as data listings. Missing data will not be imputed. 
Baseline is defined as the last non-missing value prior to each respective patient’s first dose of study 
drug. 
The Chemotherapy Arm consists of multiple agents depending on the Investigator’s choice; all these 
agents together will be considered as one Chemotherapy Arm. The statistical comparison or testing 
will only be conducted between the Combination Arm and the Chemotherapy Arm. No statistical 
comparison or testing will be conducted against or between the monotherapy arms. 
Study Populations 
• 
Intent-to-Treat (ITT) Population: The ITT Population will include all randomized patients 
regardless of the study drug received. 


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• 
Safety Population: The Safety Population will include all randomized patients who 
received any exposure to nemvaleukin, pembrolizumab, or Investigator’s choice 
chemotherapy. 
• 
Pharmacodynamic Population: The Pharmacodynamic Population will consist of all 
patients who received at least 1 dose of nemvaleukin, pembrolizumab, or Investigator’s 
choice chemotherapy and have at least 1 available post-baseline pharmacodynamic 
measurement. 
• 
Pharmacokinetic Population: The PK Population will consist of all patients who received 
at least 1 dose of nemvaleukin or pembrolizumab and have at least 1 measurable serum 
concentration of nemvaleukin or pembrolizumab at any scheduled PK time point. 
Patient Disposition 
The number of patients in the ITT Population and the reasons for discontinuation will be summarized. 
Patient disease and baseline characteristics will be summarized using frequency distribution or 
descriptive statistics, as appropriate. 
Demographics and baseline characteristics such as age, race, weight, ECOG status, prior line(s) of 
therapy, vital signs, and clinical laboratory data will be summarized with descriptive statistics. 
Medical history (including cancer history) will be summarized. 
Antitumor Activity (Efficacy) Analyses 
Antitumor activity analyses will be based on the ITT Population, unless specified otherwise. 
Antitumor activity and efficacy data (including ORR, DCR, DOR, PFS, TTR, and OS) will be 
summarized. 
Evaluation of antitumor outcomes will be based on both central review and Investigator review of the 
radiographic measurements as defined according to RECIST v1.1.  
Analysis of Primary Efficacy Endpoint: OS 
The primary endpoint was changed from PFS to OS in protocol version 5.0 because it is considered 
the most appropriate primary endpoint to objectively demonstrate clinical benefit in the target 
population (El Bairi et al, 2023). 
OS is defined as the time from randomization to death due to any cause. For patients without 
documentation of death, patients will be censored at the last known contact date or the date of study 
cut-off, whichever comes earlier. 
The treatment difference in survival will be assessed by the stratified log-rank test, and p-value will be 
reported. A stratified Cox proportional hazard model will be used for modeling the treatment effect 
between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, respectively). The Efron 
method will be used for handling the ties. The hazard ratio (HR) and its associated 95% confidence 
interval (CI) will be reported. 
OS will be displayed by Kaplan-Meier curves. Median OS and its 95% CI will be provided. The 
1-year and 2-year OS rate will be estimated using the Kaplan-Meier method. 
A statistical comparison will be conducted between the Combination Arm (Arm 1) and the 
Chemotherapy Arm (Arm 4); the monotherapy arms (either nemvaleukin alone or pembrolizumab 
alone) are included in the study for reference only.  
The statistical hypothesis test, where HR is: 
H0 (Null Hypothesis): HR (combination/chemotherapy) = 1 
Ha (Alternative Hypothesis): HR (combination/chemotherapy) < 1 


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Analysis of Secondary Efficacy Endpoints 
Progression-Free Survival: 
PFS is defined as the time from randomization to the first documentation of objective tumor 
progression (by RECIST v1.1) or death due to any cause. 
For patients who have PD while on study treatment, the date of disease progression will be the date of 
the first assessment at which PD is objectively documented per RECIST v1.1 by the Investigator. If 
the patient discontinues study treatment for reasons other than documented PD per RECIST v1.1, then 
the date of disease progression will be the date of the first assessment at which PD is objectively 
documented per RECIST v1.1 by the Investigator during the Follow-Up Period and prior to start of 
new anticancer treatment. Death is considered as a confirmed PD event. In case PD or death are 
observed immediately after 2 or more missed consecutive tumor assessments, PFS will be censored at 
the date of the last tumor assessment immediately before 2 or more missed consecutive tumor 
assessments. All remaining patients will be censored at the last known date at which the patient was 
considered progression-free. 
A stratified Cox proportional hazard model will be used for modeling the treatment effect between the 
Combination and the Chemotherapy arms (Arm 1 and Arm 4, respectively). The Efron method will be 
used for handling the ties. The HR and its associated 95% CI will be reported. 
The median PFS will be provided along with the 95% CI. In addition, Kaplan-Meier curves will be 
provided. The 6-month, 9-month, or 1-year PFS rate will be estimated using the Kaplan-Meier 
method. 
Objective Response Rate: 
ORR is defined as the proportion of patients in the analysis population who have a CR or PR. 
The best overall response is the best response recorded after initiation of study treatment until initial 
documented disease progression or start of a new anticancer treatment, whichever occurs first, taking 
into account the requirements for confirmation of CR or PR, unless otherwise specified. 
The analysis of ORR between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, 
respectively) will be conducted by the Cochran-Mantel-Haenszel (CMH) test based on randomization 
stratification factors. The ORR difference and its associated 95% CI will be reported.  
Duration of Response: 
DOR is defined as the time from the first documentation of CR or PR to the first documentation of 
objective tumor progression or death due to any cause. Patients who never achieve CR or PR prior to 
starting any new anticancer treatment will be excluded from the analysis. DOR is based on a 
non-randomized subset of patients (specifically, patients who achieve an objective response). 
Therefore, a formal hypothesis testing will not be performed for this endpoint. 
The distribution of DOR will be estimated using the Kaplan-Meier method. The median estimate of 
DOR will be provided along with 95% CI. Kaplan-Meier curves will also be provided. 
The censoring rule for DOR is the same as that of PFS. 
Disease Control Rate: 
DCR is defined as the proportion of patients with objective evidence of CR, PR, or stable disease 
(SD). For SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 6 weeks. 
DCR will be analyzed using the CMH test based on randomization stratification factors. The DCR 
difference and its associated 95% CI will be reported. 
 
 


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Time to Response: 
TTR is defined as the time from randomization to the first documentation of CR or PR. Patients who 
never achieve CR or PR prior to starting any new anticancer treatment will be excluded from the 
analysis. No censoring observation will occur by definition. TTR is based on a non-randomized subset 
of patients (specifically, patients who achieve an objective response); therefore, formal hypothesis 
testing will not be performed for this endpoint. Comparisons between treatment arms will be made for 
descriptive purposes. 
Cancer Antigen 125 Response: 
CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline and the 
response must be confirmed and maintained for at least 28 days. The number of responders will be 
analyzed using the CMH test based on randomization stratification factors. The response difference 
and its associated 95% CI will be reported. 
In addition, the change from baseline value in CA-125 will be summarized with descriptive statistics. 
Safety Analyses 
The safety endpoints will be analyzed based on the Safety Population. Safety evaluations will be 
based on AEs, vital signs, weight, clinical laboratory tests, and ECGs. Safety data (AEs, vital sign 
measurements, ECGs, and clinical laboratory results) will be summarized using descriptive statistics 
for all treatment arms. Reported AE terms will be coded using the Medical Dictionary for Regulatory 
Activities Preferred Terms and System Organ Classes and graded using National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE). 
TEAEs are defined as AEs that that have an onset on or after the day of the first dose of study drug or 
increases in severity after the first dose of study drug. TEAEs will be summarized by system organ 
class, preferred term, severity grade, and by relationship to study drug (nemvaleukin, pembrolizumab, 
both nemvaleukin and pembrolizumab, or chemotherapy). The summary tables will include the 
number and percentage of patients with TEAEs overall, by system organ class, and by preferred terms 
within each system organ class. Similar tables will be prepared for AEs of special interest, serious 
AEs (SAEs), TEAEs leading to treatment discontinuation, and additional categories of AEs as defined 
in the Statistical Analysis Plan. Disease progression will not be captured as an AE or SAE. Death due 
to disease progression will not be captured as an SAE. 
Results of vital signs and clinical laboratory tests will be summarized by visit for the absolute value 
and by change from baseline. In addition, hematologic and chemistry laboratory parameters will be 
graded according to the NCI CTCAE where applicable. The shifts from baseline NCI CTCAE grades 
to maximum and final post-baseline grades will be assessed. 
Patient-reported Outcomes: Health-related Quality of Life 
Evaluation of HRQoL will be based on the analyses of the FACT-O and EQ-5D-5L questionnaire 
items and scales. 
Sample Size Considerations 
The primary endpoint was changed from PFS to OS in protocol version 5.0; therefore, the sample size 
was recalculated based on OS assumptions. 
Approximately 366 patients are planned to be randomized in a 1:1 ratio into the Combination and the 
Chemotherapy arms (Arm 1 and Arm 4, respectively). It is expected that approximately 286 deaths 
will have been observed between the Combination and the Chemotherapy arms at the final OS 
analysis. The study has an approximate 85% power to detect an OS HR of 0.7 (the Combination arm 
versus the Chemotherapy arm at an alpha level of 2.5% (1-sided). The sample size calculation is based 
on the following assumptions: 1) 2.5% alpha is allocated to the OS endpoint; 2) OS follows an 
exponential distribution with a median of 10 months and 14.3 months in the Chemotherapy arm and 


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Combination arm, respectively; 3) the HR is 0.7, corresponding to a 4.3 month increase in the median 
OS; 4) an enrollment period of 25 months; and 5) a yearly dropout rate of 5%. 
Under protocol version 5.0, approximately 450 patients are planned, including approximately 
366 patients planned across Arm 1 and Arm 4 (approximately 183 patients in each arm). Under 
protocol version 5.0, no additional patients will be enrolled in the pembrolizumab monotherapy or 
nemvaleukin monotherapy arms (Arm 2 and Arm 3, respectively). 
Multiple Comparisons/ Multiplicity 
The overall type I error for this study is controlled at 2.5% (1-sided), fully allocated to OS. The 
statistical comparison is only performed between the Combination and Chemotherapy arms (Arm 1 
and Arm 4, respectively).  
The Lan-DeMets O’Brien-Fleming alpha-spending function is constructed to implement group 
sequential boundaries for OS hypothesis testing to control the type I error. 
Efficacy boundaries are based on the assigned type I error rate and the projected number of events at 
study milestones. The actual boundaries will be determined from the actual number of events at the 
time of the specified interim analysis using the alpha-spending function. 
There will be no type I error rate adjustment for the interim futility analyses performed for each of the 
monotherapy arms since the monotherapy arms are not included for any statistical comparisons. 
Interim Analyses 
The interim analyses planned in this study are described below. All the analyses will be conducted by 
an independent statistician under the guidance of an IDMC. The Sponsor’s study team members will 
be blinded for any aggregate antitumor efficacy data or results by assigned treatment group during the 
study conduct. More details can be found in the IDMC charter. 
Interim futility analysis of ORR in each monotherapy arm 
The monotherapy arms (either nemvaleukin alone or pembrolizumab alone) are included in the study 
as reference arms to isolate the component effect; thus, no statistical comparison or testing will be 
conducted against or between the monotherapy arms. 
Interim analyses will be conducted separately when the 24th patient enrolls into the nemvaleukin 
monotherapy arm and the 12th patient enrolls into the pembrolizumab monotherapy arm; these 
analyses will be conducted by an independent statistician. The interim analysis on the ORR will 
provide a statistical recommendation for early stopping due to futility. The pembrolizumab 
monotherapy arm (Arm 2) met its pre-specified futility criteria at the planned futility analysis and was 
closed to enrollment as of 31 Aug 2023, per the recommendation of the IDMC. 
The stopping boundary is summarized below. 
Monotherapy Arm: 
Interim Analysis at:  
Recommend Stopping Enrollment if:  
Pembrolizumab 
Monotherapy Arm 
(closed as of 
31 Aug 2023) 
First 12 dosed patients 
0 or 1 response (confirmed PR or CR) 
Nemvaleukin 
Monotherapy Arm 
First 24 dosed patients  
0 response (confirmed or unconfirmed PR 
or CR or durable SD lasting for ≥3 months) 
If the futility criteria are met, further enrollment into the arm will stop; patients in the arm receiving 
benefit (SD or better) may remain on study until progression. Crossover to another treatment arm is 
not allowed. (Note: all patients who progress at any time will be immediately discontinued from 
treatment.) 


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There will be no type I error rate adjustment at the primary efficacy analysis caused by this futility 
analysis, as the monotherapy arms are not included for any statistical comparisons. 
Interim Analysis of OS 
One planned efficacy interim analysis of OS will be performed when approximately 215 death events 
(at approximately 75% information fraction) are observed in the 2 arms (the Combination and the 
Chemotherapy arms).  
Subgroup Analyses 
Subgroup analyses relevant to baseline characteristics and disease will be performed (eg, prior 
treatments, ECOG status, biomarkers, stratification factors, age, region, race, disease stage, and 
number of prior lines of therapy). 
 


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Table 2: 
Schedule of Assessments for Arms 1 and 3 (Arm 1 Nemvaleukin + Pembrolizumab; Arm 3 Nemvaleukin 
Monotherapy) 
Procedure (Arms 1 and 3) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 
1 Year 
Cycles After 
1 Year 
EOT
** 
30-Day 
Safety 
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Comments 
Cycle Day 
1 
2 3 4 5 8 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 +7 
±7 
Pre-SCN informed consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D −35 to D −22; if needed to allow sufficient 
time for PD-L1 testing 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed by the Investigator;  
must be met ≤10 days before C1D1 
Demographics and medical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication, procedures, 
and anticancer therapy(ies) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decision of Investigator’s 
choice chemotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 statusb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed by central laboratory using tumor 
tissue sample at SCN; local assessment can be 
used in some cases b 
Tumor assessmentc 
X 
q6w 
q6w 
q12w 
Xd 
Xd 
Xd 
q6w (±7 days) from C1D1 dose during the 
1st year, and q12w (±7 days) thereafter 
CA-125c 
X 
q6w 
q6w 
q12w 
 
 
 
Tumor tissue samplee 
Xe 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
At SCN required for central PD-L1 status; 
may be collected before SCN using 
pre-SCN ICF; D8 refers to C2 only 
Physical examination 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Full exam at SCN; focused/directed exam 
while on treatment 
Vital signsg 
X 
X X X X X 
 
X 
X X X X X X X X X 
X 
X 
 
At nemvaleukin predose, end of infusion 
(±5 min), and at 0.5 hr (±5 min), 1 hr 
(±15 min) and 2 hr (±15 min) post-infusion 
Weight and heighth 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X X 
 
X 
 
X 
X 
X 
 
Weight and height at C1D1 ≤10 days; 
weight only on other dosing days 


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Procedure (Arms 1 and 3) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 
1 Year 
Cycles After 
1 Year 
EOT
** 
30-Day 
Safety 
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Comments 
Cycle Day 
1 
2 3 4 5 8 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 +7 
±7 
ECOG status 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Single ECG 
X 
as clinically indicated 
X 
 
 
 
LVEF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1D1 ≤10 days; only when PLD was selected 
as physician’s choice of chemotherapy 
Hematologyi 
X 
Xi 
 
X 
 
X 
 
X 
 
 
 
X X 
 
 
 
 
X 
 
 
10 to 3 days prior to C1D1 
Biochemistryi 
X 
Xi 
 
X 
 
X 
 
X 
 
 
 
X X 
 
 
 
 
X 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Xj 
Xj 
Local laboratory; 30-day Safety FU and 
LTFU tests only applicable to sites in France 
and Norway 
Urinalysisi k 
X 
Xi 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
10 to 3 days prior to C1D1; 
C4, and then every 4 cycles 
Thyroid test (TSH, total T3 or 
free T3, and free T4)  
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
10 to 3 days prior to C1D1; 
after SCN, TSH at each cycle, T3 and T4 only 
if needed; after 1 year, every 3 cycles 
Adrenal function test 
(cortisol and ACTH) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
10 to 3 days prior to C1D1; 
at each cycle in the 1st year;  
after 1 year, every 3 cycles 
Coagulation panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR and aPTT; 10 to 3 days prior to C1D1 
EQ-5D-5Ll m 
 
X 
 
 
 
 
 
q6w 
q12w 
X 
X 
Xm 
Before any study-related 
discussions or procedures 
FACT-Ol 
 
X 
 
 
 
X 
 
X 
 
 
 
 
q12w 
X 
X 
 
Administration of nemvaleukinn 
 
X X X X X 
 
X 
X X X X X X X X X 
 
 
 
6 µg/kg; 21-day cycles;  
30-min IV infusion 
ctDNAo 
 
X 
 
 
 
 
Xf Xo 
 
 
 
 
 
 
 
 
 
X 
 
 
Do not collect after C3; 
predose (C1D1 ≤10 days; CxD1 ≤24 hr) 
Immunophenotyping (PBMC, 
TBNK, Treg) 
 
Xo 
 
 
 
 
Xf Xo 
 
 
 
 
 
 
 
 
 
X 
 
 


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Procedure (Arms 1 and 3) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 
1 Year 
Cycles After 
1 Year 
EOT
** 
30-Day 
Safety 
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Comments 
Cycle Day 
1 
2 3 4 5 8 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 +7 
±7 
Serum for soluble proteinsp 
(PIP and IL-2RA) 
 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D1: predose (C1D1 ≤10 days; C2D1 ≤24 hr) 
and at 2 hr postdose (nemvaleukin);  
D2: ≤2 hr predose (nemvaleukin) 
PK (nemvaleukin)  
 
X
q 
 
 
 
 
 
X
q 
 
 
 
 
X
q 
 
 
 
 
X
q 
X
q 
 
Predose (C1D1 ≤10 days; CxD1 ≤24 hr)  
and at infusion completion 
Immunogenicity (ADA) 
(nemvaleukin)  
 
Xr 
 
 
 
 
 
Xr 
 
 
 
 
Xr 
 
 
 
 
Xr 
Xr 
 
Predose (C1D1 ≤10 days; CxD1 ≤24 hr) 
AEs and concomitant meds 
X 
X X X X X 
 
X 
X X X X X X X X X 
X 
Xs 
Xs 
Concomitant meds are to be followed as long 
as AEs are followed 
Subsequent anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Overall survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
HIV, HBV, HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only applicable to sites in Czech Republic; 
local test 
ARM 1 Only 
Administration of 
pembrolizumab 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
After nemvaleukin administration; 
200 mg; 21-day cycles; 30-min IV infusion; 
for a maximum of 35 cycles (≈2 years) 
PK (pembrolizumab) 
 
X
t 
 
 
 
 
 
X
t 
 
 
 
 
 
 
 
 
 
X
t 
X
t 
 
D1 of C1, C2, C4, and C8;  
predose (C1D1 ≤10 days; CxD1 ≤24 hr);  
and at infusion completion 
Immunogenicity (ADA) 
(pembrolizumab) 
 
Xu 
 
 
 
 
 
Xu 
 
 
 
 
 
 
 
 
 
Xu 
Xu 
 
D1 of C1, C2, C4, and C8;  
predose (C1D1 ≤10 days; CxD1 ≤24 hr) 
ACTH=adrenocorticotropic hormone, ADA=antidrug antibody, AE=adverse event, aPTT=activated partial thromboplastin time, C=Cycle, CA-125=cancer 
antigen 125, CPS=combined positive score, ctDNA=circulating tumor DNA, D=Day, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, 
eCRF=electronic case report form, EOC=epithelial ovarian cancer, EOT=end of treatment, EQ-5D-5L=EuroQol 5 Dimension 5-Level, FACT-O=Functional 
Assessment of Cancer Therapy – Ovarian, FU=follow-up, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, 
ICF=Informed Consent Form, IL-2RA=interleukin 2 receptor alpha, INR=international normalized ratio, IV=intravenous, LTFU=long-term follow-up, 
LVEF=left ventricular ejection fraction, meds=medications, PBMC=peripheral blood mononuclear cell, PD-L1=programmed death ligand 1, PIP=pro-
inflammatory panel, PK=pharmacokinetics, PLD=pegylated liposomal doxorubicin, PR=partial response, q12w=every 12 weeks, q3=every 3, q6w=every 
6 weeks, RECIST=Response Evaluation Criteria in Solid Tumors, SAE=serious adverse event, SCN=Screening, TBNK=T cell, B cell, and natural killer cell, 


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Treg=regulatory T-cell, T3=triiodothyronine, T4=thyroxine, TSH=thyroid-stimulating hormone, US=United States, VAS=Visual Analog Scale, 
WOCBP=women of childbearing potential. 
* Assessments on D1 have a visit window of −3 days unless noted otherwise in the table footnote or in the comments’ column. 
** EOT Visit should be scheduled within 7 days from the day a decision was made to discontinue study treatment. 
***The Safety Follow-up assessments apply to all patients dosed and will be scheduled at least 30 days (±7 days) following the EOT Visit. 
****Patients will be contacted by the Investigator for phone visits during the Long-term Follow-up Period. Assessment to be performed every 3 months (±15 days) 
or more frequently to assess for survival status starting from the EOT Visit, for up to 3 years from first dose of study drug. 
a The assessment window for the pre-screening ICF is D −35 to D −22. Pre-screening ICF can be completed before main ICF to allow sufficient time for 
assessment of PD-L1 by central laboratory in advance. This time should take into account the time needed to schedule and perform the biopsy and the transit 
time to the central laboratory. 
b Central PD-L1 results are required for randomization. Under extreme circumstances the medical monitor may pre-approve the use of local PD-L1 result for 
randomization if: (1) tissue was submitted for central assessment, and the laboratory was given at least 10 business days to run the assay, but the results did not 
become available in the expected timeframe for randomization; and (2) local assessment was performed using DAKO 22C3 assay and allows PD-L1 status 
categorization (CPS ≥10 vs CPS <10). 
c Tumor assessment should include all appropriate procedures to document the full extent of the patient’s neoplastic disease according to RECIST v1.1. The 
same procedure used to define measurable or non-measurable lesions must be used throughout the study for each patient. Tumor assessment and CA-125 
should be performed q6w (±7 days) from C1D1 dose during the first year of study participation and q12w (±7 days) thereafter. Scans used for screening disease 
assessment that were performed previously as part of routine clinical management are acceptable to use if they are of diagnostic quality, have anatomic extent 
to cover the entirety of disease involvement, were performed within 28 days prior to C1D1, and the method used for the scan can be maintained throughout the 
study. When applicable, tumor assessment should be performed prior to dosing. A confirmatory scan for the first demonstration of a PR or better should be 
performed no sooner than 4 weeks (highly recommended) and no later than 6 weeks. See Section 10.2.1 for details on acceptable methods of tumor imaging 
and guidance for patients with history or suspicion of brain metastases. 
d For patients who complete treatment or discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring 
their disease status by radiologic imaging q6w (Year 1 from start of treatment) or every 12 weeks (Years 2+ from start of treatment) from C1D1 until (1) the 
assessment of progressive disease, (2) the initiation of new anticancer therapy(ies), (3) withdrawal of consent, (4) death, or (5) end of study, whichever occurs 
first. 
e Fresh (newly obtained) or archival tumor tissue sample may be collected for central immunohistochemistry testing of PD-L1 status prior to Screening after 
signing the pre-screening ICF. A tumor tissue sample collected at Screening (fresh biopsy) is preferred. Alternatively, a patient may provide a tumor tissue 
sample from prior cytoreductive surgery, or any archival tumor tissue collected since diagnosis of EOC. If surgery is planned during the study, collection of 
tissue and blood samples is recommended with appropriate documented consent under the optional biopsy collection procedures. 
f In patients with accessible lesions, an additional on-treatment tumor biopsy is highly recommended on C2D8 (+4 days). See Section 10.4.2.2 for additional 
details. An additional immunophenotyping sample and an additional ctDNA sample will also be collected in patients with the optional biopsy performed on 
C2D8 (+4 days). Both the additional immunophenotyping sample and the additional ctDNA sample should be collected on the same day (±3 days) as the 
optional biopsy. For all patients randomized at sites in the US and Canada, a mandatory immunophenotyping sample will be collected on C1D8 (+2 days) and 
C2D8 (+2 days). 
g Vital signs include blood pressure, pulse, respiratory rate, and body temperature. 
h Height will be obtained at Screening only. Weight may be recorded within 10 days before expected dosing on C1D1 and within 3 days before dosing for other 
dosing days. 


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i Hematology, biochemistry, and urinalysis samples must be collected 10 to 3 days prior to expected C1D1 (ie, from D −10 to D −3) for central laboratory results 
to be available for review to assess eligibility. Local laboratory results can be used for eligibility if the central laboratory test results are at risk of arriving 
outside the expected timeframe for randomization. In this case, sites are still required to review central laboratory results when they become available. If a 
central laboratory result does not meet the eligibility criteria but the local laboratory result does, the local laboratory result that supports the patient’s eligibility 
should be entered into the eCRF. Otherwise, samples must be collected as noted in the schedule of assessments. 
j All WOCBP must have a negative pregnancy test (serum or urine) performed by local laboratory within 3 days before the first dose of every cycle. If 
pregnancy testing is performed within these intervals before dosing, sampling does not need to be repeated on the day of dosing. For patients at sites in France 
and Norway: after treatment discontinuation, pregnancy testing in heterosexually active WOCBP must continue to be assessed monthly for 30 days in Arm 3 
and for 120 days in Arm 1. 
k If dipstick assessment result is abnormal, relevant work-up is per Investigator discretion (see Appendix 3). 
l The questionnaires must be completed before any study-related discussions or procedures. 
m VAS only. Investigator or appropriately delegated designee will record the patient’s response. 
n Any time nemvaleukin is administered, antipyretics are recommended prior to administration, during dosing of IV nemvaleukin, and subsequently as needed. 
Patient must be well hydrated prior to start of treatment. 
o ctDNA and immunophenotyping samples are to be collected on C1D1 (within 10 days before dosing and can be drawn on different days than safety labs [ie, 
hematology, biochemistry, and urinalysis]), C2D1 and C3D1 (within 24 hours before dosing), and EOT. 
p For D1, serum for soluble proteins (PIP) is to be collected for C1 within 10 days before dosing on D1 and the samples must be drawn on the same day as other 
laboratory samples (ie, ctDNA and immunophenotype), for all other cycles within 24 hours before dosing on D1, and at 2 hours (±15 minutes) postdose. For 
D2, serum for soluble proteins is to be collected within 2 hours (±15 minutes) prior to dosing. IL-2RA is only to be collected predose on C1D1. 
q Samples will be collected on D1 of each cycle for Cycles 1-8 as follows: for C1 within 10 days before dosing on D1 and must be drawn on the same day as 
other laboratory samples, for all other cycles within 24 hours before dosing on D1 and at the completion of the 30-minute (±5 minutes) nemvaleukin infusion. 
Additional samples will be collected at EOT and at Safety Follow-up. Samples should be drawn from the arm opposite of the arm used to infuse study drug. Do 
not take samples from a central line used to infuse study drug. 
r Samples will be collected on D1 of each cycle for Cycles 1-8 as follows: for C1 within 10 days before dosing on D1 and must be drawn on the same day as 
other laboratory samples (ie, ctDNA, immunophenotyping, and PK), for all other cycles within 24 hours before dosing on D1. Additional samples will be 
collected at EOT and at Safety Follow-up. Samples should be drawn from the arm opposite of the arm used to infuse study drug. Do not take samples from a 
central line used to infuse study drug. 
s During the Follow-up Period, patients will be contacted by the Investigator for in-office visit/phone visits to review any AEs/SAEs and concomitant 
medications at 30 days after the EOT. In addition, SAEs will be collected for patients in Arm 1 through 90 days after the EOT during Survival Follow-up visits. 
For all patients, if new anticancer therapy is initiated, AE and concomitant medication collection will stop. Any AE or SAE with an onset 30 days (Arm 3) or 
90 days (Arm 1) after the EOT will not be collected or reported unless the Investigator assesses the event to be related to the study drug. 
t Applies to Arm 1 only. Samples will be collected on D1 of Cycles 1, 2, 4, and 8 as follows: predose (for C1 within 10 days before dosing on D1 and must be 
drawn on the same day as other laboratory samples [ie, ctDNA, immunophenotyping, and PK], for all other cycles, D1 samples can be drawn within 24 hours 
before the start of pembrolizumab infusion) and at the completion of the pembrolizumab infusion (+30 minutes). Additional samples will be collected at EOT 
and Safety Follow-up. Samples should be drawn from the arm opposite of the arm used to infuse study drug. Do not take samples from a central line used to 
infuse study drug. 
u Applies to Arm 1 only. Samples will be collected on D1 of Cycles 1, 2, 4, and 8 as follows: predose, for C1 within 10 days before dosing on D1 and must be 
drawn on the same day as other laboratory samples, for all other cycles samples can be drawn within 24 hours before the start of pembrolizumab infusion. 


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Protocol ALKS 4230-007 Version 5.0 
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22 
Additional samples will be collected at EOT and Safety Follow-up. Samples should be drawn from the arm opposite of the arm used to infuse study drug. Do 
not take samples from a central line used to infuse study drug. 
 


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23 
Table 3: 
Schedule of Assessments for Arm 2 (Pembrolizumab Monotherapy) 
Procedure (Arm 2) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 
1 Year 
Cycles After 
1 Year 
EOT 
** 
30-Day 
Safety  
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Comments 
Cycle Day 
1 2 3 4 5 8 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
+7 
±7 
Pre-SCN informed consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D −90 to D −22; if needed to allow sufficient 
time for PD-L1 testing 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed by the Investigator,  
must be met ≤10 days before C1D1 
Demographics and medical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication, procedures, 
and anticancer therapy(ies) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decision of Investigator’s 
choice chemotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 statusb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed by central laboratory using tumor 
tissue sample at SCN; local assessment can be 
used in some cases b 
Tumor assessmentc 
X 
q6w 
q6w 
q12w 
Xd 
Xd 
Xd 
q6w (±7 days) from C1D1 dose during the 
1st year, and q12w (±7 days) thereafter 
CA-125c 
X 
q6w 
q6w 
q12w 
 
 
 
Tumor tissue samplee 
Xe 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
At SCN required for central PD-L1 status; 
may be collected before SCN using 
pre-SCN ICF; D8 refers to C2 only 
Physical examinationg 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Full exam at SCN; focused/directed exam 
while on treatment 
Vital signsh 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
At predose, end of infusion (±5 min), at 
0.5 hr (±5 min), and 1 hr (±15 min) 
Weight and heighti 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Weight and height at C1D1 ≤10 days; 
weight only on other dosing days 
ECOG status 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 


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Procedure (Arm 2) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 
1 Year 
Cycles After 
1 Year 
EOT 
** 
30-Day 
Safety  
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Comments 
Cycle Day 
1 2 3 4 5 8 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
+7 
±7 
Single ECG 
X 
as clinically indicated 
X 
 
 
 
LVEF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1D1 ≤10 days; only when PLD was selected 
as physician’s choice of chemotherapy 
Hematologyj 
X 
Xj 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
10 to 3 days prior to C1D1 
Biochemistryj 
X 
Xj 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Xk 
Xk 
Local laboratory; 30-day Safety FU and 
LTFU tests only applicable to sites in France 
and Norway 
Urinalysisj l 
X 
Xj 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
10 to 3 days prior to C1D1; 
C4, and then every 4 cycles 
Thyroid test (TSH, total T3 or 
free T3, and free T4) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
10 to 3 days prior to C1D1; 
after SCN, TSH at each cycle, T3 and T4 only 
if needed; after 1 year, every 3 cycles 
Adrenal function test 
(cortisol and ACTH) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
10 to 3 days prior to C1D1; 
at each cycle in the 1st year;  
after 1 year, every 3 cycles 
Coagulation panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR and aPTT; 10 to 3 days prior to C1D1 
EQ-5D-5Lm n 
 
X 
 
 
 
 
 
q6w 
q12w 
X 
X 
Xn 
Before any study-related discussions or 
procedures 
FACT-Om 
 
X 
 
 
 
 
 
X 
 
 
 
 
q12w 
X 
X 
 
Administration of 
pembrolizumab 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
200 mg; 21-day cycles; 30-min IV infusion; 
for a maximum of 35 cycles (≈2 years) 
ctDNAo 
 
X 
 
 
 
 
Xf Xo 
 
 
 
 
 
 
 
 
 
X 
 
 
D8 refers to C2 only; do not collect after C3; 
predose (C1D1 ≤10 days; CxD1 ≤24 hr) 
Immunophenotyping (PBMC, 
TBNK, Treg) 
 
Xo  
 
 
 
Xf Xo 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum for soluble proteinsp 
(PIP and IL-2RA) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predose (C1D1 ≤10 days; C2D1 ≤24 hr) 
and at 2 hr postdose 


Mural Oncology, Inc. 
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Procedure (Arm 2) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 
1 Year 
Cycles After 
1 Year 
EOT 
** 
30-Day 
Safety  
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Comments 
Cycle Day 
1 2 3 4 5 8 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 
+7 
±7 
AEs and concomitant meds 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Xq 
Xq 
Concomitant meds are to be followed as long 
as AEs are followed 
Subsequent anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Overall survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
HIV, HBV, HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only applicable to sites in Czech Republic; 
local test 
ACTH=adrenocorticotropic hormone, AE=adverse event, aPTT=activated partial thromboplastin time, C=Cycle, CA-125=cancer antigen 125, CPS=combined 
positive score, ctDNA=circulating tumor DNA, D=Day, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case report 
form, EOC=epithelial ovarian cancer, EOT=end of treatment, EQ-5D-5L=EuroQol 5 Dimension 5-Level, FACT-O=Functional Assessment of Cancer Therapy 
– Ovarian, FU=follow-up, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, ICF=Informed Consent Form, 
IL-2RA=interleukin 2 receptor alpha, INR=international normalized ratio, IV=intravenous, LTFU=long-term follow-up, LVEF=left ventricular ejection 
fraction, meds=medications, PBMC=peripheral blood mononuclear cell, PD-L1=programmed death ligand 1, PIP=pro-inflammatory panel, PLD=pegylated 
liposomal doxorubicin, PR=partial response, q12w=every 12 weeks, q3=every 3, q6w=every 6 weeks, RECIST=Response Evaluation Criteria in Solid Tumors, 
SAE=serious adverse event, SCN=Screening, TBNK=T cell, B cell, and natural killer cell, Treg=regulatory T-cell, T3=triiodothyronine, T4=thyroxine, 
TSH=thyroid-stimulating hormone, VAS=Visual Analog Scale, WOCBP=women of childbearing potential. 
* Assessments on D1 have a visit window of −3 days unless noted otherwise in the table footnote or in the comments’ column. 
** EOT Visit should be scheduled within 7 days from the day a decision was made to discontinue study treatment. 
***The Safety Follow-up assessments apply to all patients dosed and will be scheduled at least 30 days (±7 days) following the EOT Visit. 
****Patients will be contacted by the Investigator for phone visits during the Long-term Follow-up Period. Assessment to be performed every 3 months (±15 days) 
or more frequently to assess for survival status starting from the EOT Visit, for up to 3 years from first dose of study drug. 
a The assessment window for the pre-screening ICF is D −90 to D −22. Pre-screening ICF can be completed before main ICF to allow sufficient time for 
assessment of PD-L1 by central laboratory in advance. This time should take into account the time needed to schedule and perform the biopsy and the transit 
time to the central laboratory. 
b Central PD-L1 results are required for randomization. Under extreme circumstances the medical monitor may pre-approve the use of local PD-L1 result for 
randomization if: (1) tissue was submitted for central assessment, and the laboratory was given at least 10 business days to run the assay, but the results did not 
become available in the expected timeframe for randomization; and (2) local assessment was performed using DAKO 22C3 assay and allows PD-L1 status 
categorization (CPS ≥10 vs CPS <10). 
c Tumor assessment should include all appropriate procedures to document the full extent of the patient’s neoplastic disease according to RECIST v1.1. The 
same procedure used to define measurable or non-measurable lesions must be used throughout the study for each patient. Tumor assessment and CA-125 
should be performed q6w (±7 days) from C1D1 dose during the first year of study participation and q12w (±7 days) thereafter. Scans used for screening disease 
assessment that were performed previously as part of routine clinical management are acceptable to use if they are of diagnostic quality, have anatomic extent 
to cover the entirety of disease involvement, were performed within 28 days prior to C1D1, and the method used for the scan can be maintained throughout the 


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study. When applicable, tumor assessment should be performed prior to dosing. A confirmatory scan for the first demonstration of a PR or better should be 
performed no sooner than 4 weeks (highly recommended) and no later than 6 weeks. See Section 10.2.1 for details on acceptable methods of tumor imaging 
and guidance for patients with history or suspicion of brain metastases. 
d For patients who complete treatment or discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring 
their disease status by radiologic imaging q6w (Year 1 from start of treatment) or every 12 weeks (Years 2+ from start of treatment) from C1D1 until (1) the 
assessment of progressive disease, (2) the initiation of new anticancer therapy(ies), (3) withdrawal of consent, (4) death, or (5) end of study, whichever occurs 
first. 
e Fresh (newly obtained) or archival tumor tissue sample may be collected for central immunohistochemistry testing of PD-L1 status prior to Screening after 
signing pre-screening ICF. A tumor tissue sample collected at Screening (fresh biopsy) is preferred. Alternatively, a patient may provide a tumor tissue sample 
from prior cytoreductive surgery, or any archival tumor tissue collected since diagnosis of EOC. If surgery is planned during the study, collection of tissue and 
blood samples is recommended with appropriate documented consent under the optional biopsy collection procedures. 
f In patients with accessible lesions, an additional on-treatment tumor biopsy is highly recommended on C2D8 (+4 days). See Section 10.4.2.2 for additional 
details. An additional immunophenotyping sample and an additional ctDNA sample will also be collected in patients with the optional biopsy performed on 
C2D8 (+4 days). Both the additional immunophenotyping sample and the additional ctDNA sample should be collected on the same day (±3 days) as the 
optional biopsy. 
g A full physical examination is to be performed at Screening. Focused/directed physical examinations for the areas of disease or AEs are to be performed at all 
other visits. 
h Vital signs include blood pressure, pulse, respiratory rate, and body temperature. On days when study drug is not administered, vital signs may be collected at 
any time. 
i Height will be obtained at Screening only. Weight may be recorded within 10 days before expected dosing on C1D1 and within 3 days before dosing for other 
dosing days. 
j Hematology, biochemistry, and urinalysis samples must be collected 10 to 3 days prior to expected C1D1 (ie, from D −10 to D −3) for central laboratory results 
to be available for review to assess eligibility. Local laboratory results can be used for eligibility if the central laboratory test results are at risk of arriving 
outside the expected timeframe for randomization. In this case, sites are still required to review central laboratory results when they become available. If a 
central laboratory result does not meet the eligibility criteria but the local laboratory result does, the local laboratory result that supports the patient’s eligibility 
should be entered into the eCRF. Otherwise, samples must be collected as noted in the schedule of assessments.  
k All WOCBP must have a negative pregnancy test (serum or urine) performed by local laboratory within 3 days before the first dose of every cycle. If 
pregnancy testing is performed within these intervals before dosing, sampling does not need to be repeated on the day of dosing. For patients at sites in France 
and Norway: after treatment discontinuation, pregnancy testing in heterosexually active WOCBP must continue to be assessed monthly for 120 days. 
l If dipstick assessment result is abnormal, relevant work-up is per Investigator discretion (see Appendix 3). 
m The questionnaires must be completed before any study-related discussions or procedures. 
n VAS only. Investigator or appropriately delegated designee will record the patient’s response. 
o ctDNA and immunophenotyping samples are to be collected on C1D1 (within 10 days before dosing and can be drawn on different days than safety labs [ie, 
hematology, biochemistry, and urinalysis]), C2D1 and C3D1 (within 24 hours before dosing), and EOT. 
p For D1, serum for soluble proteins (PIP) is to be collected for C1 within 10 days before dosing on D1 and the samples must be drawn on the same day as other 
laboratory samples (ie, ctDNA and immunophenotype), for all other cycles within 24 hours before dosing on D1, and at 2 hours (±15 minutes) postdose. 
IL-2RA is only to be collected predose on C1D1. 
q During the Follow-up Period, patients will be contacted by the Investigator for in-office visit/phone visits to review any AEs/SAEs and concomitant 
medications at 30 days after the EOT. In addition, SAEs will be collected through 90 days after the EOT during Survival Follow-up visits. For all patients, if 


Mural Oncology, Inc. 
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new anticancer therapy is initiated, AE and concomitant medication collection will stop. Any AE or SAE with an onset 90 days after the EOT will not be 
collected or reported unless the Investigator assesses the event to be related to the study drug. 
 


Mural Oncology, Inc. 
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Table 4: 
Schedule of Assessments for Arm 4 (Investigator’s Choice Chemotherapy) 
Procedure (Arm 4) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 1 Year 
Cycles After 1 Year 
EOT 
** 
30-Day 
Safety 
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Cycle Day 
1 
2 
3 
4 
5 
8 
15 22 
1 
2 
3 
4 
5 
8 
15 22 
1 
2 
3 
4 
5 
8 
15 
22 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 
±1 
+7 
±7 
Pre-SCN informed consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteriab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication, procedures, 
and anticancer therapy(ies) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decision of Investigator’s 
choice chemotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 statusc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessmentd 
X 
q6w 
q6w 
q12w 
Xe 
Xe 
Xe 
CA-125d 
X 
q6w 
q6w 
q12w 
 
 
 
Tumor tissue samplec 
Xc 
 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Vital signsh 
X 
per institutional standard or labeling information of chemotherapy regimen 
X 
X 
 
ECOG status 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Single ECG 
X 
as clinically indicated 
X 
 
 
Pregnancy testi 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xi 
Xi 
Thyroid testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adrenal function testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisk l 
X 
Xk 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
 
 
X 
X 
 
Coagulation panelj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Mural Oncology, Inc. 
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Procedure (Arm 4) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 1 Year 
Cycles After 1 Year 
EOT 
** 
30-Day 
Safety 
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Cycle Day 
1 
2 
3 
4 
5 
8 
15 22 
1 
2 
3 
4 
5 
8 
15 22 
1 
2 
3 
4 
5 
8 
15 
22 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 
±1 
+7 
±7 
EQ-5D-5Lm n 
 
X 
 
 
 
 
 
 
 
q6w 
q12w 
X 
X 
Xn 
FACT-Om 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
q12w 
X 
X 
 
ctDNAo 
 
X 
 
 
 
 
Xf 
 
 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Subsequent anticancer 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Overall survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV, HBV, HCV tests (sites 
in Czech Republic only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM 4 PLD (40 mg/m2); 28-day Cycles (Administered on D1) 
Administration of PLD 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight and heightp 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Hematologyk 
X 
Xk 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Biochemistryk 
X 
Xk 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
LVEF 
X 
Xq 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
Xq 
 
 
 
 
 
 
 
X 
 
 
AEs and concomitant meds 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xr 
Xr 
ARM 4 paclitaxel (80 mg/m2); 28-day Cycles (Administered on D1, D8, D15, and D22) 
Administration of paclitaxel 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Weight and heightp 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
Hematologyk 
X 
Xk 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
Biochemistryk 
X 
Xk 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
AEs and concomitant meds 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
Xr 
Xr 


Mural Oncology, Inc. 
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Procedure (Arm 4) 
SCN 
Cycles 1 and 2 
Cycle 3+ up to 1 Year 
Cycles After 1 Year 
EOT 
** 
30-Day 
Safety 
FU*** 
LTFU 
q3 
Months 
(±15d) 
**** 
Cycle Day 
1 
2 
3 
4 
5 
8 
15 22 
1 
2 
3 
4 
5 
8 
15 22 
1 
2 
3 
4 
5 
8 
15 
22 
Visit Window 
(days) 
D −21 
to −1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
* 
−3 ±1 ±1 ±1 ±1 ±1 ±1 
±1 
+7 
±7 
ARM 4 topotecan 4 mg/m2; 28-day Cycles (Administered on D1, D8, and D15) 
Administration of topotecan 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
Weight and heightp 
X 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
 
X 
X 
 
Hematologyk 
X 
Xk 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Biochemistryk 
X 
Xk 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
AEs and concomitant meds 
X 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
 
X 
Xr 
Xr 
ARM 4 topotecan 1.25 mg/m2; 21-day Cycles (Administered D1 to D5) 
Administration of topotecan 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Weight and heightp 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Hematologyk 
X 
Xk 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Biochemistryk 
X 
Xk 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
AEs and concomitant meds 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Xr 
Xr 
ARM 4 gemcitabine 1,000 mg/m2; 21-day Cycles (Administered D1 and D8) 
Administration of 
gemcitabine 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Weight and heightp 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Hematologyk 
X 
Xk 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Biochemistryk 
X 
Xk 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
AEs and concomitant meds 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
Xr 
Xr 
ACTH=adrenocorticotropic hormone, AE=adverse event, C=Cycle, CA-125=cancer antigen 125, CPS=combined positive score, ctDNA=circulating tumor DNA, 
D=Day, ECG=electrocardiogram, ECHO=echocardiogram, ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case report form, EOC=epithelial 
ovarian cancer, EOT=end of treatment, EQ-5D-5L=EuroQol 5 Dimension 5-Level, FACT-O=Functional Assessment of Cancer Therapy – Ovarian, 
FU=follow-up, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, ICF=Informed Consent Form, IV=intravenous, 
LTFU=long-term follow-up, LVEF=left ventricular ejection fraction, meds=medications, MUGA=multiple gated acquisition, PD-L1=programmed death 


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ligand 1, PLD=pegylated liposomal doxorubicin, PR=partial response, q12w=every 12 weeks, q3=every 3, q6w=every 6 weeks, RECIST=Response Evaluation 
Criteria in Solid Tumors, SAE=serious adverse event, SCN=Screening, T3=triiodothyronine, T4=thyroxine, TSH=thyroid-stimulating hormone, VAS=Visual 
Analog Scale, WOCBP=women of childbearing potential. 
* Assessments on D1 have a visit window of −3 days unless noted otherwise in the table footnote. 
** EOT Visit should be scheduled within 7 days from the day a decision was made to discontinue study treatment. 
***The Safety Follow-up assessments apply to all patients dosed and will be scheduled at least 30 days (±7 days) following the EOT Visit. 
****Patients will be contacted by the Investigator for phone visits during the Long-term Follow-up Period. Assessment to be performed every 3 months (±15 days) 
or more frequently to assess for survival status starting from the EOT Visit, for up to 3 years from first dose of study drug. 
a The assessment window for the pre-screening ICF is D −35 to D −22. Pre-screening ICF can be completed before main ICF to allow sufficient time for 
assessment of PD-L1 by central laboratory in advance. This time should take into account the time needed to schedule and perform the biopsy and the transit 
time to the central laboratory. 
b Eligibility requirements should be assessed by the Investigator and must be met within 10 days prior to expected C1D1. 
c Fresh (newly obtained) or archival tumor tissue sample may be collected for central immunohistochemistry testing of PD-L1 status prior to SCN after signing 
the pre-screening ICF. A tumor tissue sample collected at SCN (fresh biopsy) is preferred. Alternatively, a patient may provide a tumor tissue sample from 
prior cytoreductive surgery, or any archival tumor tissue collected since diagnosis of EOC. If surgery is planned during the study, collection of tissue and blood 
samples is recommended with appropriate documented consent under the optional biopsy collection procedures. Central PD-L1 results are required for 
randomization. Under extreme circumstances the medical monitor may pre-approve the use of local PD-L1 result for randomization if: (1) tissue was submitted 
for central assessment, and the laboratory was given at least 10 business days to run the assay, but the results did not become available in the expected 
timeframe for randomization; and (2) local assessment was performed using DAKO 22C3 assay and allows PD-L1 status categorization (CPS ≥10 vs CPS 
<10). 
d Tumor assessment should include all appropriate procedures to document the full extent of the patient’s neoplastic disease according to RECIST v1.1. The 
same procedure used to define measurable or non-measurable lesions must be used throughout the study for each patient. Tumor assessment and CA-125 
should be performed q6w (±7 days) from C1D1 dose during the first year of study participation and q12w (±7 days) thereafter. Scans used for screening disease 
assessment that were performed previously as part of routine clinical management are acceptable to use if they are of diagnostic quality, have anatomic extent 
to cover the entirety of disease involvement, were performed within 28 days prior to C1D1, and the method used for the scan can be maintained throughout the 
study. When applicable, tumor assessment should be performed prior to dosing. A confirmatory scan for the first demonstration of a PR or better should be 
performed no sooner than 4 weeks (highly recommended) and no later than 6 weeks. See Section 10.2.1 for details on acceptable methods of tumor imaging 
and guidance for patients with history or suspicion of brain metastases. 
e For patients who complete treatment or discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring 
their disease status by radiologic imaging q6w (Year 1 from start of treatment) or every 12 weeks (Years 2+ from start of treatment) from C1D1 until (1) the 
assessment of progressive disease, (2) the initiation of new anticancer therapy(ies), (3) withdrawal of consent, (4) death, or (5) end of study, whichever occurs 
first. 
f In patients with accessible lesions, an additional on-treatment tumor biopsy is highly recommended on C2D8 (+4 days). See Section 10.4.2.2 for additional 
details. An additional ctDNA sample will also be collected in patients with the optional biopsy performed on C2D8 (+4 days). The additional ctDNA sample 
should be collected on the same day (±3 days) as the optional biopsy. 
g A full physical examination is to be performed at SCN. Focused/directed physical examinations for the areas of disease or AEs are to be performed at all other 
visits. 
h Vital signs include blood pressure, pulse, respiratory rate, and body temperature. For Investigator’s choice chemotherapy, monitor vital signs per institutional 
standard or labeling information of chemotherapy regimen. 


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i All WOCBP must have a negative pregnancy test (serum or urine) performed by local laboratory within 3 days before the first dose of every cycle. If 
pregnancy testing is performed within these intervals before dosing, sampling does not need to be repeated on the day of dosing. For patients at sites in France 
and Norway: after treatment discontinuation, pregnancy testing in heterosexually active WOCBP must continue to be assessed monthly for the recommended 
duration of the contraception in the approved label and/or institutional guidelines for the specific Investigator’s choice chemotherapy. 
j Samples for thyroid test, adrenal function test, and coagulation panel are to be collected 10 to 3 days prior to expected C1D1 (ie, from D −10 to D −3). TSH, 
total T3 or free T3, free T4, total cortisol, and ACTH are to be collected at Screening for all patients. 
k Hematology, biochemistry, and urinalysis samples must be collected on the same day 10 to 3 days prior to expected C1D1 (ie, from D −10 to D −3) for central 
laboratory results to be available for review to assess eligibility. Local laboratory results can be used for eligibility if the central laboratory test results are at 
risk of arriving outside the expected timeframe for randomization. In this case, sites are still required to review central laboratory results when they become 
available. If a central laboratory result does not meet the eligibility criteria but the local laboratory result does, the local laboratory result that supports the 
patient’s eligibility should be entered into the eCRF. Otherwise, samples can be collected as noted in the schedule of assessments. Mid-cycle laboratory 
assessments beyond C3 can be performed as per institutional guidance. 
l Urinalysis must be collected at C4D1 and every 4 cycles thereafter (ie, C8D1, C12D1, etc). If dipstick assessment result is abnormal, relevant work-up is per 
Investigator discretion (see Appendix 3). 
m The questionnaires must be completed prior to any study related discussions with patients and prior to any study procedures (when applicable).  
n VAS only. Investigator or appropriately delegated designee will record the patient’s response. 
o ctDNA is to be collected on C1D1 (within 10 days before dosing and can be drawn on different days than safety labs [ie, hematology, biochemistry, and 
urinalysis]), C2D1 and C3D1 (within 24 hours before dosing), and EOT. 
p Height will be obtained at Screening only. Weight may be recorded within 10 days before expected dosing on C1D1 and within 3 days before dosing for other 
dosing days. 
q LVEF assessment at baseline can be done during the Screening Period within 10 days of expected C1D1 for patients where PLD was selected as physician’s 
choice of chemotherapy. C1D1 assessment does not need to be performed if baseline assessment was performed as per protocol. On-treatment LVEF 
assessment is to be performed every 4 cycles (ie, C5D1, C9D1, etc; within 3 days of the first dose of the cycle) and only applies to patients who are randomized 
to Investigator’s Choice Chemotherapy Arm to receive PLD. The same assessment technique (MUGA or ECHO) should be conducted throughout treatment. If 
patient LVEF drops below normal or by at least 15% from baseline, treatment with PLD should be discontinued. 
r During the Follow-up Period, patients will be contacted by the Investigator for in-office visit/phone visits to review any AEs/SAEs and concomitant 
medications at 30 days after the EOT. For all patients, if new anticancer therapy is initiated, AE and concomitant medication collection will stop. Any AE or 
SAE with an onset 30 days after the EOT will not be collected or reported unless the Investigator assesses the event to be related to the Investigator’s choice 
chemotherapy. 
Note: Investigator’s choice chemotherapy to be administered as follows: for PLD (40 mg/m2), Day 1 of 28-day cycles, 1 mg/min for Cycle 1, and 60-minute 
infusions for Cycles 2+; for paclitaxel (80 mg/m2; 60-minute IV infusion), Days 1, 8, 15, and 22 of 28-day cycles; for topotecan, either Days 1, 8, and 15 of 
28-day cycles (4 mg/m2; 30-minute IV infusion) or Days 1 through 5 of 21-day cycles (1.25 mg/m2; 30-minute IV infusion); for Gemcitabine (1,000 mg/m2; 
30-minute IV infusion), Day 1 and 8 of 21-day cycles. 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS ...........................................................................................33 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................39 
5. 
INTRODUCTION ......................................................................................................43 
5.1. 
Ovarian Background and Current Treatment Standards .............................................43 
5.2. 
Nemvaleukin Preliminary Clinical Evidence .............................................................44 
5.3. 
Background on Nemvaleukin .....................................................................................45 
5.4. 
Background on Pembrolizumab .................................................................................46 
5.5. 
Rationale for Dose Selection ......................................................................................47 
5.6. 
Benefit-Risk Assessment ............................................................................................48 
5.7. 
Clinical Hypotheses ....................................................................................................48 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................49 
7. 
STUDY POPULATION .............................................................................................51 
7.1. 
Patient Inclusion Criteria ............................................................................................51 
7.2. 
Patient Exclusion Criteria ...........................................................................................53 
7.3. 
Study Requirements and Restrictions .........................................................................56 
7.3.1. 
Contraception and Pregnancy .....................................................................................56 
7.3.1.1. 
Patient Eligibility Requirements .................................................................................56 
7.3.1.2. 
Contraception and Egg Donation Requirements During the Study ............................56 
7.3.1.3. 
If a Pregnancy Occurs .................................................................................................56 
7.3.2. 
Concomitant and Prohibited Medications ..................................................................57 
7.3.3. 
Meals and Dietary Restrictions ...................................................................................58 
7.4. 
Screen Failures ............................................................................................................58 
7.5. 
Patient Discontinuation ...............................................................................................59 
7.5.1. 
Patient Discontinuation From Treatment ....................................................................59 
7.5.2. 
Patient Discontinuation From Study ...........................................................................59 
7.5.3. 
Minimizing Unnecessary Withdrawal ........................................................................60 
7.5.4. 
End of Study/Study Termination ................................................................................60 


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7.6. 
Replacement of Patients .............................................................................................61 
8. 
STUDY DESIGN .......................................................................................................62 
8.1. 
Overall Study Design ..................................................................................................62 
8.2. 
Number of Patients Planned .......................................................................................63 
8.3. 
Duration of Treatment and Duration of Study ............................................................64 
9. 
STUDY DRUGS ........................................................................................................65 
9.1. 
Administration of Study Drugs ...................................................................................65 
9.2. 
Guidance for Study Drug Administration...................................................................67 
9.2.1. 
Guidance for Nemvaleukin Administration ................................................................67 
9.2.2. 
Guidance for Pembrolizumab Administration ............................................................68 
9.2.3. 
Guidance for Chemotherapy Administration ..............................................................68 
9.3. 
Study Drug Adjustments, Stopping Rules, and Dose Delays .....................................68 
9.3.1. 
Dosing Modification and Management of Toxicities .................................................68 
9.3.1.1. 
Nemvaleukin: Dosing Modification and Management of Toxicities .........................69 
9.3.1.2. 
Pembrolizumab: Dosing Modification and Management of Toxicities .....................74 
9.3.1.3. 
PLD: Dosing Modification and Management of Toxicities .......................................80 
9.3.1.4. 
Paclitaxel: Dosing Modification and Management of Toxicities ...............................82 
9.3.1.5. 
Topotecan: Dosing Modification and Management of Toxicities ..............................84 
9.3.1.6. 
Gemcitabine: Dosing Modification and Management of Toxicities ..........................86 
9.3.2. 
Delay of Cycles for Other Reasons ............................................................................88 
9.4. 
Treatment Adherence ..................................................................................................88 
9.5. 
Storage, Handling, Accountability, and Disposal of Study Drugs .............................88 
10. 
STUDY PROCEDURES AND ASSESSMENTS......................................................89 
10.1. 
Study Procedures Descriptions ...................................................................................89 
10.1.1. 
Informed Consent .......................................................................................................89 
10.1.2. 
Eligibility Review .......................................................................................................89 
10.1.3. 
Demographics and Medical History ...........................................................................89 
10.1.4. 
Prior and Concomitant Medication Review ...............................................................89 
10.1.4.1. 
Prior and Concomitant Medication .............................................................................90 
10.1.4.2. 
Anticancer Medication ................................................................................................90 
10.1.5. 
Randomization ............................................................................................................90 
10.2. 
Efficacy Assessments .................................................................................................91 
10.2.1. 
Tumor Assessment ......................................................................................................91 


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10.2.2. 
Survival Status ............................................................................................................92 
10.3. 
Safety Assessments .....................................................................................................92 
10.3.1. 
Adverse Event Monitoring .........................................................................................92 
10.3.1.1. 
Definition of Adverse Event .......................................................................................93 
10.3.1.2. 
Definition of Nemvaleukin Adverse Events of Special Interest (AESIs) ...................94 
10.3.1.3. 
Definition of Serious Adverse Event ..........................................................................95 
10.3.1.4. 
Relationship to Study Drug or Procedure ...................................................................95 
10.3.1.5. 
Monitoring and Recording of Adverse Events ...........................................................96 
10.3.1.6. 
Reporting of Serious Adverse Events and Pregnancy ................................................97 
10.3.2. 
Physical Examination .................................................................................................97 
10.3.3. 
Vital Signs, Electrocardiograms, and Left Ventricular Ejection Fraction ..................97 
10.3.4. 
Laboratory Assessments .............................................................................................98 
10.3.4.1. 
Hematology, Biochemistry, Urinalysis, and Coagulation ..........................................98 
10.3.4.2. 
Pregnancy Testing ......................................................................................................98 
10.3.5. 
Eastern Cooperative Oncology Group Status .............................................................98 
10.4. 
Assessment of Pharmacokinetics, Pharmacodynamics, and Immunogenicity ...........98 
10.4.1. 
Pharmacokinetics ........................................................................................................99 
10.4.2. 
Pharmacodynamics and Biomarkers...........................................................................99 
10.4.2.1. 
Blood-Based Biomarkers ............................................................................................99 
10.4.2.2. 
Tumor Tissue Assessment ..........................................................................................99 
10.4.3. 
Immunogenicity ........................................................................................................100 
11. 
STATISTICS ............................................................................................................101 
11.1. 
Sample Size Considerations .....................................................................................101 
11.2. 
Analysis Populations ................................................................................................101 
11.3. 
Statistical Methodology ............................................................................................102 
11.3.1. 
Demographics and Baseline Characteristics .............................................................102 
11.3.2. 
Patient Disposition ....................................................................................................102 
11.3.3. 
Drug Administration and Compliance ......................................................................103 
11.3.4. 
Handling of Missing Data .........................................................................................103 
11.3.5. 
Multiplicity Adjustments ..........................................................................................103 
11.3.6. 
Concomitant Medications .........................................................................................103 
11.3.7. 
Efficacy Analyses .....................................................................................................103 
11.3.7.1. 
Primary Efficacy Analyses .......................................................................................103 


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11.3.7.2. 
Secondary Efficacy Analyses ...................................................................................105 
11.3.8. 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses .....................107 
11.3.8.1. 
Pharmacokinetic Analyses ........................................................................................107 
11.3.8.2. 
Pharmacodynamic Analyses .....................................................................................107 
11.3.8.3. 
Immunogenicity Analyses ........................................................................................108 
11.3.9. 
Safety Analyses ........................................................................................................108 
11.3.9.1. 
General Considerations .............................................................................................108 
11.3.9.2. 
Adverse Events .........................................................................................................108 
11.3.9.3. 
Clinical Laboratory Parameters ................................................................................109 
11.3.9.4. 
Vital Signs and ECG .................................................................................................110 
11.3.9.5. 
ECOG Status .............................................................................................................110 
11.3.10. 
Patient-Reported Outcomes: Health-Related Quality of Life ...................................110 
11.4. 
Randomization/Method of Assigning Patients to Treatment ....................................111 
11.5. 
Blinding and Independent Data Monitoring Committee ..........................................112 
11.6. 
Interim Analyses .......................................................................................................112 
11.7. 
Subgroup Analysis ....................................................................................................113 
12. 
REFERENCES .........................................................................................................114 
13. 
APPENDICES ..........................................................................................................118 
13.1. 
Appendix 1: Contraception Definitions ....................................................................118 
13.2. 
Appendix 2: New York Heart Association Heart Disease Classifications ...............120 
13.3. 
Appendix 3: Clinical Laboratory Assessments .........................................................121 
13.4. 
Appendix 4: Eastern Cooperative Oncology Group Status ......................................122 
13.5. 
Appendix 5: COVID-19 Structured Risk Analysis ..................................................123 
13.5.1. 
COVID-19 Related Risks .........................................................................................123 
13.5.2. 
Risk for Patients and Study Staff ..............................................................................123 
13.5.3. 
Impact of the Investigational Drug on COVID-19 ...................................................125 
13.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations ..................126 
13.6.1. 
Regulatory and Ethical Considerations ....................................................................126 
13.6.2. 
Financial Disclosure .................................................................................................127 
13.6.3. 
Informed Consent Process ........................................................................................127 
13.6.4. 
Confidentiality of Data .............................................................................................128 
13.6.5. 
Committees Structure ...............................................................................................128 
13.6.6. 
Data Quality Assurance ............................................................................................129 


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13.6.6.1. 
Study Monitoring ......................................................................................................129 
13.6.6.2. 
Audits and Inspections ..............................................................................................129 
13.6.7. 
Source Documents ....................................................................................................129 
13.6.8. 
Study and Site Closure..............................................................................................130 
13.6.9. 
Use of Information and Publication Policy ..............................................................130 
13.6.10. 
Major Protocol Deviations ........................................................................................130 
 
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
Schedule of Assessments for Arms 1 and 3 (Arm 1 Nemvaleukin + 
Pembrolizumab; Arm 3 Nemvaleukin Monotherapy) ................................................17 
Table 3: 
Schedule of Assessments for Arm 2 (Pembrolizumab Monotherapy) .......................23 
Table 4: 
Schedule of Assessments for Arm 4 (Investigator’s Choice Chemotherapy) ............28 
Table 5: 
List of Abbreviations and Definition of Terms ..........................................................39 
Table 6: 
Study Objectives and Endpoints .................................................................................49 
Table 7: 
Study Drug Description and Administration ..............................................................66 
Table 8: 
Recommendations for Nemvaleukin Dosing Modifications for Drug-Related 
Toxicity (Excluding Adverse Events of Special Interest) ..........................................70 
Table 9: 
Recommendations for Nemvaleukin Dosing Modifications for Drug-Related 
Adverse Events of Special Interest .............................................................................71 
Table 10: Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab Monotherapy or 
Immuno-Oncology Combinations ..............................................................................75 
Table 11: Dose Reduction Levels of Pegylated Liposomal Doxorubicin ...................................80 
Table 12: Guidance for Pegylated Liposomal Doxorubicin Dosing Modifications ...................81 
Table 13: Summary of Pegylated Liposomal Doxorubicin Dose Reductions in Case of 
Mucositis and Cutaneous Toxicity .............................................................................82 
Table 14: Dose Reduction Levels of Paclitaxel ..........................................................................82 
Table 15: Guidance for Paclitaxel Dosing Modifications ...........................................................83 
Table 16: Dose Reduction Levels of Topotecan .........................................................................84 
Table 17: Guidance for Topotecan Dosing Modifications (Weekly and 5-Day Dosing 
Schedules) ...................................................................................................................85 
Table 18: Dose Reduction Levels of Gemcitabine .....................................................................86 
Table 19: Guidance for Gemcitabine Dosing Modifications ......................................................87 


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Table 20: Adverse Event Causality Guidelines ..........................................................................96 
Table 21: Censoring Rule for Overall Survival Analysis .........................................................104 
Table 22: Censoring Rule for Progression-Free Survival .........................................................106 
Table 23: Stopping Boundary for Interim Futility Analysis of Objective Response Rate 
in Monotherapy Arms ...............................................................................................112 
Table 24: Summary of Number of Events and Decision Guidance at the Planned 
Overall Survival Analyses ........................................................................................113 
Table 25: New York Heart Association Heart Disease Classifications ....................................120 
Table 26: Clinical Laboratory Assessments .............................................................................121 
Table 27: Eastern Cooperative Oncology Group Status ...........................................................122 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................63 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Table 5: 
List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ALK-P 
alkaline phosphatase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BRCA 
breast cancer gene 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CA-125 
cancer antigen 125 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLS 
capillary leak syndrome 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CPS 
combined positive score 
CR 
complete response 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CSA 
clinical study agreement 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte associated protein 4 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 


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Abbreviation 
Definition 
DOR 
duration of response 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol 5 Dimension 5-Level 
FACT-O 
Functional Assessment of Cancer Therapy – Ovarian 
FDA 
Food and Drug Administration 
G-CSF 
granulocyte colony-stimulating factor 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IL 
interleukin 
IL-2R 
interleukin-2 receptor 
INR 
international normalized ratio 
irAE 
immune-related adverse event 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ITT 
Intent-to-Treat 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
natural killer 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly adenosine diphosphate-ribose polymerase 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PLD 
pegylated liposomal doxorubicin 
PR 
partial response 
PROC 
platinum-resistant ovarian cancer 
PT 
preferred term 
q12w 
every 12 weeks 
q21d 
every 21 days 
q3w 
every 3 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human IL-2 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
stable disease 
SOA 
Schedule of Assessments 


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Abbreviation 
Definition 
SOC 
System Organ Class 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TMB 
tumor mutational burden 
Tregs 
regulatory T cells 
TSH 
thyroid stimulating hormone 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 
VAS 
Visual Analogue Scale 
WOCBP 
women of childbearing potential 


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5. 
INTRODUCTION 
5.1. 
Ovarian Background and Current Treatment Standards 
Ovarian, fallopian tube, and primary peritoneal cancers identified as EOCs are life-threatening 
diseases and comprise the seventh most common cause of cancer mortality in women (Bray et al, 
2018). In the US in 2020, an estimated 21,750 women will be newly diagnosed with ovarian 
cancer, and an estimated 13,940 women will die from the disease (Siegel et al, 2020). Standard 
frontline treatment for EOC is platinum-based chemotherapy with or without an antiangiogenic, 
such as bevacizumab, which may be followed by maintenance therapy with bevacizumab, a 
PARP inhibitor, or both, depending on biomarker status. Antiangiogenic agents 
(eg, bevacizumab) and PARP inhibitors (eg, olaparib, niraparib etc) are the 
2 molecularly-targeted therapies approved in recurrent EOC worldwide. The additional treatment 
option for EOC has increased the survival of patients with recurrent EOC and at least half of 
them will likely receive more than 3 lines of therapy. There is high unmet medical need in 
patients with no standard treatment option after their third line (3+ disease) treatment. More 
efforts to identify new treatment options for this increasing number of patients with “chronic” 
disease are needed (Pujade-Lauraine and Combe 2016). Activity of the platinum-based regimens 
is clinically meaningful for a majority of patients, although disease recurrence is common, and 
most patients will eventually become resistant to the platinum therapy. These patients are known 
as recurrent, PROC patients. For patients who become resistant to or who are refractory to 
platinum, the standard of care is single-agent non-platinum chemotherapy, which offers a low 
likelihood of durable response. In the most recent AURELIA study, physician’s choice 
chemotherapy (PLD, paclitaxel, topotecan, or gemcitabine) generated objective responses in 
12% of PROC patients with a PFS of 3.4 months (Pujade-Lauraine et al, 2014). 
Recently, there have been multiple failed Phase 3 studies in the EOC and PROC spaces with 
novel targeted agents and immune checkpoint inhibitors. The FORWARD I study showed a 
higher response rate for mirvetuximab soravtansine than for chemotherapy (22% vs 12%, 
P=0.015), but failed to meet its primary endpoint of PFS (HR=0.98, P=0.897) or OS (HR=0.815, 
P=0.248); a selected subgroup with high folate receptor expression showed promising activity, 
and a larger study is ongoing to confirm these results (Immunogen Inc 2019; Moore et al, 2019). 
In early studies, anti-PD-1 or anti-PD-L1 monotherapies were also shown to be ineffective for 
treating EOC, in general; these therapies generate objective responses in <15% of 
platinum-sensitive and -resistant ovarian cancer patients, with a median PFS of 2.1 months 
(Gonzalez-Martin and Sanchez-Lorenzo 2019; Matulonis et al, 2019). Most recently, 3 large 
Phase 3 studies treating EOC with immune checkpoint inhibitors failed to meet their primary 
endpoints. IMagyn050/GOG 3015/ENGOT-OV39, a Phase 3 study in the frontline setting, 
recently reported failure to meet its primary endpoint of PFS for atezolizumab plus bevacizumab 
and chemotherapy, versus bevacizumab and chemotherapy alone (Moore et al, 2020). In 
addition, in the PROC disease state, avelumab alone or in combination with standard of care 
(PLD) did not improve survival in the Phase 3 JAVELIN 200 study (Pujade-Lauraine et al, 
2019). NINJA, a Phase 3 study of monotherapy nivolumab versus gemcitabine or PLD 
(GEM/PLD), also failed to improve OS (HR=1.03, P=0.808) (Omatsu et al, 2020). Median PFS 
was 2.04 (95% CI, 1.91 to 2.20) months with nivolumab and 3.84 (95% CI, 3.58 to 4.17) months 
with GEM/PLD (HR=1.46; 95% CI, 1.15 to 1.85; P=0.002), while ORR was 8% (95% CI, 3.5 to 
13.9) versus 13% (95% CI, 7.6 to 20.8), respectively. Additionally, a Phase 2 study of 


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pembrolizumab, KEYNOTE-100, showed modest responses of 7.4% to 9.9%, with a median 
PFS of only 2.1 months; higher PD-L1 expression was correlated with higher response 
(Matulonis et al, 2019). There are a number of immune checkpoint inhibitor studies ongoing in 
EOC that will further determine if checkpoint inhibitors alone or in combination with standard of 
care or other novel agents have the potential to treat the disease (Grywalska et al, 2019). These 
ongoing studies and studies like these will allow us to further understand the potential of 
immunotherapy in the treatment of EOC. 
Epithelial ovarian cancers, in general, have immunogenic properties, with over half of patients 
demonstrating tumor-infiltrating lymphocytes. Tumors with expression of PD-L1 show enhanced 
response to PD-1/L1 inhibitors relative to those without expression (Kandalaft et al, 2011). 
Interestingly, EOC tumors with immune infiltrates typically demonstrate a high proportion of 
Tregs, which could establish immunosuppressive phenotypes. Additionally, EOC tumors often 
harbor a lower TMB and frequency of PD-L1 expression as compared to other tumor types more 
responsive to checkpoint inhibition therapies (eg, bladder cancer, melanoma). The available data 
suggest that single-agent checkpoint inhibitors show only modest activity in EOC (Gatalica et al, 
2014; Woo et al, 2001). Additionally, smaller studies of high dose IL-2 generated response rates 
of approximately 25% in platinum-pretreated ovarian cancer patients (Edwards et al, 1997; Vlad 
et al, 2010). The most promising immunotherapy activity to date in ovarian cancer is with the 
combination of the anti-PD-1 nivolumab and the anti-CTLA-4 ipilimumab in platinum-resistant 
disease. This combination therapy was associated with an ORR of 34% (doubling the results of 
nivolumab monotherapy), yet there was no significant difference in PFS between the 
combination therapy and nivolumab alone, thus demonstrating a lack of true durability of 
responses (Zamarin et al, 2020). 
5.2. 
Nemvaleukin Preliminary Clinical Evidence 
Intravenous nemvaleukin alfa (‘nemvaleukin’, ALKS 4230) monotherapy and the combination 
of IV nemvaleukin with pembrolizumab have shown preliminary evidence of clinical benefit in 
multiple tumor types in the open-label Phase 1/2 ARTISTRY-1 (ALK4230-A101) study. 
In Part A of the ARTISTRY-1 study (dose escalation, data cut-off 29 Oct 2021), approximately 
46 patients were treated with escalating dose levels from 0.1 to 10 μg/kg. Of the 46 patients, 
12 heavily pretreated patients (median of 3 [1 to 8] prior lines of therapy) were treated with 
nemvaleukin monotherapy at 6 µg/kg (recommended Phase 2 dose). The patients enrolled at the 
6 μg/kg dose level had a mix of tumor indications, including 4 patients with melanoma, 
3 patients with colorectal carcinoma, and 1 patient with RCC. SD by RECIST v1.1 was reported 
in patients enrolled at dose levels of 0.3 μg/kg to 8 μg/kg. Among the 12 patients treated in the 
6 µg/kg dose level cohort, 9 were evaluable for disease assessment, and the best response among 
them was SD by RECIST v1.1 in 4 patients. 
In Part B of the ARTISTRY-1 study (dose expansion, monotherapy, data cut-off 29 Oct 2021), 
74 patients (47 melanoma, 27 RCC) were treated with nemvaleukin monotherapy at 6 μg/kg 
(recommended Phase 2 dose). Of the 46 evaluable patients with melanoma (30 cutaneous 
melanoma, 6 mucosal melanoma, and 10 other melanomas; per RECIST v1.1), 4 patients 
achieved a PR: 1 confirmed PR in mucosal melanoma, 1 unconfirmed PR in mucosal melanoma, 
1 confirmed PR in cutaneous melanoma, and 1 unconfirmed PR in cutaneous melanoma. 
Two additional PRs occurred after the data cut-off date: 1 confirmed PR and 1 PR awaiting 


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confirmation, both in patients with cutaneous melanoma. In addition, SD was observed in 
31 patients with melanoma (2 with mucosal melanoma). Of the 22 evaluable patients with RCC, 
4 achieved a PR (3 confirmed and 1 unconfirmed) and 10 patients had SD. 
In Part C of the ARTISTRY-1 study (dose expansion, combination therapy, data cut-off 
29 Oct 2021), 165 patients (including 42 rollover patients from Part A and Part B) received a 
combination of nemvaleukin and pembrolizumab (the majority of the patients received 
3 or 6 ug/kg of nemvaleukin q3w and 200 mg of pembrolizumab q3w). Of those, 137 patients 
had evaluable on-study disease assessment scans (per RECIST v1.1). Of the 137 evaluable 
patients, there were 4 CRs, 18 PRs, and 60 SDs. As of 29 Oct 2021, 43 patients were still on 
treatment in the ARTISTRY-1 study. 
As of 29 Oct 2021, 15 heavily pretreated ovarian cancer patients were enrolled in Cohort 1 
(Part C). Of the 15 patients, 14 patients were evaluable and had PROC. Among the 14 evaluable 
PROC patients, there were 2 CRs, 2 PRs (1 confirmed, 1 unconfirmed), and 1 prolonged SD 
reported resulting in an ORR of 28.6% and a DCR of 71.4%. The median DOR was 53.4 weeks 
among the PROC patients. 
As of 21 Apr 2022, nemvaleukin safety data has been evaluated in 279 patients for the IV route 
of administration − both as monotherapy and in combination with pembrolizumab 
(ARTISTRY-1, ARTISTRY-3, ARTISTRY-6, and ION-01-ALKS 4230 studies). The most 
frequent (≥30%) TEAEs occurring at 6 μg/kg q21d nemvaleukin (IV administration) were 
Pyrexia, Neutropenia, Chills, Nausea, Fatigue, Anaemia, Aspartate aminotransferase increased, 
and Alanine aminotransferase increased. In general, a similar incidence of TEAEs was reported 
for both the IV monotherapy and IV combination therapy. 
Overall, the safety profile of nemvaleukin IV is consistent with its mechanism of action and is 
similar to what is expected in the relapsed/refractory solid cancer patient population. 
Nemvaleukin IV as monotherapy and in combination with pembrolizumab was well tolerated. 
No apparent added toxicity was observed for nemvaleukin in combination with pembrolizumab 
compared with pembrolizumab alone. 
5.3. 
Background on Nemvaleukin 
Nemvaleukin is an engineered fusion protein composed of a circularly permuted IL-2 and 
IL-2Rα designed to selectively activate the intermediate-affinity IL-2R, but not the high-affinity 
IL-2R. The IL-2Rα domain of nemvaleukin serves to sterically impede the binding of 
nemvaleukin to the high-affinity IL-2R yet still allow binding to the intermediate-affinity IL-2R 
(Lopes et al, 2020a). IL-2 plays a pivotal role in immune homeostasis due to its ability to 
stimulate numerous lymphocyte subsets including NK cells, effector CD4+ and CD8+ T cells, 
and Tregs. Low concentrations of IL-2 induce signaling through the high-affinity IL-2R 
comprised of IL-2Rα, IL-2Rβ, and common γ chain (γc), preferentially expressed on Tregs. Higher 
concentrations of IL-2 are necessary to induce signaling through the intermediate-affinity IL-2R, 
composed of IL-2Rβ and γc, and predominantly expressed on memory CD8+ T cells and NK 
cells, which play an important role in driving antitumor immune responses (Sim and Radvanyi 
2014). Recombinant human IL-2 is approved for treatment of metastatic melanoma and RCC 
(Proleukin USPI), but AEs including CLS limit its therapeutic use, potentially mediated through 
interaction with the high-affinity IL-2R expressed on vascular endothelial cells (Huh et al, 2012; 
Krieg et al, 2010). Furthermore, antitumor efficacy of IL-2 may also be limited by preferential 


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expansion of immunosuppressive Tregs, which may limit anticancer activity of rhIL-2 (Malek and 
Bayer 2004). Despite the poor tolerability of immunotherapy with rhIL-2, it remains one of the 
few treatment regimens for metastatic melanoma and RCC that elicits a complete and durable 
response in a subset of patients. Thus, selective activation of the intermediate-affinity IL-2R by 
nemvaleukin has the potential to provide enhanced tumor killing as well as improved safety and 
tolerability. 
In vitro and in vivo nonclinical pharmacodynamics data support selective signaling through the 
intermediate-affinity IL-2R by nemvaleukin, leading to the activation and expansion of effector 
cells, including CD8+ T cells and NK cells, while minimizing the activation and expansion of 
immunosuppressive Tregs. Additional nonclinical data demonstrate that administration of IV or 
SC nemvaleukin results in equivalent tumor growth inhibition in a mouse syngeneic tumor 
model. Overall, preclinically, administration of nemvaleukin results in the selective activation 
and expansion of effector cells with minimal activation and expansion of immunosuppressive 
CD4+ Tregs compared to rhIL-2 (Lopes et al, 2020b). 
Harnessing of the IL-2 pathway has potential to provide benefit to patients with epithelial 
ovarian, fallopian tube, or primary peritoneal cancer based on results of a Phase 2 study of 
intraperitoneal rhIL-2 administered to patients with platinum-resistant or platinum-refractory 
ovarian cancer (Vlad et al, 2010). Of 24 patients assessed for response, there were 6 (4 complete, 
2 partial) responses for an overall response rate of 25.0% [95% CI of 11-45]. The median 
survival of the 31-patient cohort was 2.1 years (95% CI, 1.3 to 4.4), but for the 6 patients with 
responses the median survival was not reached at the time of publication (range 24 to 
120+ months). There were also significant associations between on-treatment changes in T cell 
counts and survival, suggesting that a therapy that can activate and expand effector T cell 
responses can provide benefit to patients with advanced ovarian cancer. 
5.4. 
Background on Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-1 
receptor, thus inhibiting its interaction with PD-L1 and programmed cell death 1 ligand 2. Based 
on nonclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an IV immunotherapy for advanced malignancies. KEYTRUDA® 
(pembrolizumab) is indicated for the treatment of patients across several indications. For more 
details on specific indications refer to the IB. 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T cells and the ratio of CD8+ effector 
T cells/FoxP3+ Tregs correlates with improved prognosis and long-term survival in solid 
malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; 
malignant melanoma; and RCC. Tumor-infiltrating lymphocytes can be expanded ex vivo and 
reinfused, inducing durable objective tumor responses in cancers such as melanoma (Dudley et 
al, 2005; Hunder et al, 2008). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells under 


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healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 that has been shown to negatively regulate antigen receptor signaling on 
engagement of its ligands (PD-L1 and/or programmed cell death 1 ligand 2) (Greenwald et al, 
2005; Okazaki et al, 2001). 
The structure of murine PD-1 has been resolved (Zhang et al, 2004). PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. After T cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 T cell 
signaling cascade (Chemnitz et al, 2004; Okazaki et al, 2001; Riley 2009; Sheppard et al, 2004). 
The mechanism by which PD-1 down-modulates T cell responses is similar to, but distinct from, 
that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
(Francisco et al, 2010; Parry et al, 2005). As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in epithelial ovarian, fallopian tube, or primary 
peritoneal cancer. 
5.5. 
Rationale for Dose Selection 
The selection of IV nemvaleukin dose of 6 µg/kg/day given on 5 consecutive days is based on 
several considerations, including pharmacodynamic effects on immune cell expansion, safety, 
and preliminary exposure-response analysis as well as IV nemvaleukin monotherapy activity. 
Data from the ARTISTRY-1 study was used for dose selection. Do note that current data from 
the 3 µg/kg dose level of nemvaleukin in combination with pembrolizumab is more mature as 
compared to the data from the 6 µg/kg dose level in combination with pembrolizumab in Part C 
of ARTISTRY-1 as enrollment in the 3 µg/kg in combination with pembrolizumab group started 
in December 2018, while enrollment in the 6 µg/kg in combination with pembrolizumab group 
only started in January 2020. 
• Data from Part A (dose escalation) of ARTISTRY-1 indicated that systemic exposure 
to nemvaleukin increased with increase in dose, which correlated with a 
dose-dependent increase in absolute counts of NK cells and CD8+ T cells, with a 
minimal, non-dose-dependent effect on Tregs. A greater expansion of CD8+ T cells 
and NK cells was observed at 6 µg/kg as compared with 3 µg/kg with a similar safety 
profile at 6 µg/kg. 
• Preliminary dose/exposure – response analysis indicated that higher systemic 
exposure is likely to be associated with a higher probability of observing clinical 
activity. Given the high unmet need in the PROC patient population, the 6 µg/kg dose 
is anticipated to improve the likelihood of observing beneficial clinical response with 
a manageable safety profile. 


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• Although 6 µg/kg was selected as the recommended Phase 2 dose for IV 
nemvaleukin, dose escalation continues in ARTISTRY-1 with the 8 µg/kg dose level 
being tolerated to date, thus providing additional safety margin for the selected dose. 
• Selection of 6 µg/kg was also supported by IV nemvaleukin monotherapy activity in 
both RCC and mucosal melanoma at the 6 µg/kg dose in Part B (monotherapy 
expansion) of ARTISTRY-1 with 5 objective responses observed to date. 
Taken all together, the overall benefit/risk assessment supports the selected dosing regimen for 
IV nemvaleukin 6 µg/kg/day for 5 consecutive days every 3 weeks, either as monotherapy or in 
combination with pembrolizumab (200 mg q3w) for ARTISTRY-7. 
The planned dose of pembrolizumab for this study is 200 mg q3w. Based on the totality of data 
generated in the KEYTRUDA development program, 200 mg q3w is an appropriate dose of 
pembrolizumab for adults across all indications and regardless of tumor type. To date in the 
nemvaleukin development program, the combination of nemvaleukin and pembrolizumab has 
not shown any additive toxicity to the known safety profile of either agent. Furthermore, in 
ARTISTRY-1, the ovarian cohort showed a favorable and acceptable benefit/risk profile using 
these doses and dosing regimen of nemvaleukin and pembrolizumab. 
5.6. 
Benefit-Risk Assessment 
It is believed that the selectivity of nemvaleukin for the intermediate-affinity IL-2R but not the 
high-affinity IL-2R will improve the safety and tolerability profile as compared to human 
recombinant IL-2, a therapeutic with established clinical efficacy, and may also result in 
enhanced antitumor effects against a variety of cancer types. Nemvaleukin has been evaluated in 
approximately 315 patients across the nemvaleukin development program and the emerging 
safety profile is favorable in the setting of patients with advanced solid tumors. Pembrolizumab 
is an approved agent with an established safety profile. To date in the nemvaleukin development 
program, the combination of nemvaleukin and pembrolizumab has not shown any additive 
toxicity to the known safety profile of either agent. In ARTISTRY-1, the ovarian cohort 
evaluating nemvaleukin and pembrolizumab combination regimen has shown favorable results. 
Furthermore, there exist no effective/ approved therapies for PROC, a highly unmet need. Thus, 
the benefit/risk profile evaluation of the nemvaleukin and pembrolizumab combination regimen 
in patients with PROC is favorable. 
5.7. 
Clinical Hypotheses 
The preliminary activity seen in ARTISTRY-1 together with the scientific evidence and rationale 
provided above clearly demonstrate that single-agent checkpoint inhibition is not sufficient to 
reliably achieve meaningful efficacy in EOCs. Novel immunotherapies like nemvaleukin in 
combination with a checkpoint inhibitor could provide additional immunologic stimulation to 
achieve clinically significant tumor killing, resulting in improved outcomes for these difficult to 
treat tumors. The primary study hypothesis is that the combination of nemvaleukin plus 
pembrolizumab will generate a significantly improved OS compared to current standard of care 
chemotherapies with an acceptable safety profile. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints are listed in Table 6. 
Table 6: 
Study Objectives and Endpoints 
Study Objectives 
Study Endpoints 
Primary Objective: 
• 
To evaluate the OS of nemvaleukin in 
combination with pembrolizumab as 
compared with chemotherapy in patients with 
platinum resistant ovarian cancer 
Primary Endpoint: 
• 
OS 
Secondary Objectives: 
• 
To evaluate the antitumor activity of 
nemvaleukin in combination with 
pembrolizumab as compared with 
chemotherapy 
• 
To evaluate the safety of nemvaleukin in 
combination with pembrolizumab as 
compared with chemotherapy 
Secondary Endpoints: 
• 
PFS as assessed by Investigator, based on 
RECIST v1.1 
• 
ORR as assessed by Investigator, based on 
RECIST v1.1 
• 
DCR, DOR, and TTR as assessed by Investigator, 
based on RECIST v1.1 
• 
CA-125 response as defined by the GCIG 
• 
Safety as assessed by TEAEs, clinical laboratory 
parameters, vital signs, and ECGs 
Exploratory Objectives: 
• 
To evaluate the antitumor activity of 
pembrolizumab monotherapy; to evaluate the 
antitumor activity of nemvaleukin 
monotherapy 
• 
To evaluate HRQoL 
• 
To determine if any baseline or changes in 
parameters in tumor tissue and/or peripheral 
blood may correlate to response to treatment 
with nemvaleukin in combination with 
pembrolizumab 
• 
To evaluate the PK, immunogenicity, and 
pharmacodynamic effects of nemvaleukin 
and/or pembrolizumab in this treatment 
regimen 
Exploratory Endpoints: 
• 
PFS, ORR, DOR, TTR, and OS of the monotherapy 
arms as assessed by Investigator, based on 
RECIST v1.1 
• 
HRQoL as assessed by the following PRO 
instruments: the FACT-O questionnaire and the 
EQ-5D-5L questionnaire 
• 
Pretreatment levels, on-treatment levels, and/or 
changes from pretreatment levels of the following 
parameters (in tumor specimens and/or peripheral 
blood): 
− 
CPS of PD-L1, TMB, and other relevant 
genetic and non-genetic predictive markers 
(eg, HRD, BRCA mutation) 
− 
Serum concentrations of nemvaleukin (and 
pembrolizumab as appropriate) 


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Study Objectives 
Study Endpoints 
− 
Presence of anti-nemvaleukin antibodies (and 
anti-pembrolizumab antibodies as appropriate) 
in serum 
− 
Leukocytes including, but not limited to, 
circulating CD8+ T cells, Tregs, and NK cells 
− 
Serum concentrations of interferon-γ, IL-6, 
and other soluble proteins 
BRCA=breast cancer gene, CA-125=cancer antigen 125, CD=cluster of differentiation, CPS=combined positive 
score, DCR=disease control rate, DOR=duration of response, ECG=electrocardiogram, EQ-5D-5L=EuroQol 
5 Dimension 5-Level, FACT-O=Functional Assessment of Cancer Therapy – Ovarian, GCIG=Gynecologic 
Cancer InterGroup, HRD=homologous recombination deficiency, HRQoL=health-related quality of life, 
IL=interleukin, NK=natural killer, ORR=objective response rate, OS=overall survival, PD-L1=programmed death 
ligand 1, PFS=progression-free survival, PK=pharmacokinetic(s), PRO=patient-reported outcome, 
RECIST=Response Evaluation Criteria in Solid Tumors, TEAE=treatment-emergent adverse event, TMB=tumor 
mutational burden, Tregs=regulatory T cells, TTR=time to response  
 


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7. 
STUDY POPULATION 
7.1. 
Patient Inclusion Criteria 
In order to qualify for participation in the study, patients must meet all of the following criteria. 
Inclusion criteria should be assessed by the Investigator and, when applicable (per SOA) the 
assessment should occur within 10 days prior to expected C1D1 (closer to C1D1 is highly 
recommended). 
1. Patient is female and ≥18 years of age. 
2. Patient or patient’s legal representative (as applicable per regional requirements) has 
provided written informed consent. 
3. Patient is willing and able to comply with scheduled visits, treatment schedule, laboratory 
tests, and other requirements of the study. 
4. Patient has histologically confirmed diagnosis of EOC, fallopian tube cancer, or primary 
peritoneal cancer and histology subtype: high-grade serous, endometrioid of any grade, 
clear cell. 
5. Patient has platinum-resistant/refractory disease: resistant is defined as disease 
progression within 180 days following the last administered dose of platinum therapy 
beyond first-line setting (ie, initial platinum therapy); and refractory is defined as disease 
progression or lack of response followed by disease progression while receiving the most 
recent platinum-based therapy (ie, beyond initial therapy). Patient must have progressed 
radiographically or by GCIG-defined CA-125 criteria on or after their most recent line of 
anticancer therapy beyond first-line setting. 
a. Note: Progression should be calculated from the date of the last administered dose of 
platinum therapy to the date of the radiographic imaging showing progression or the 
date progression was assessed by GCIG-defined CA-125 criteria, whichever comes 
first. 
b. Note: Patients who have primary platinum-refractory or platinum-resistant disease 
(disease progression <3 months after completion of first-line platinum-based therapy) 
are excluded (see Exclusion Criterion 1). 
6. Patient must have received at least 1 prior line of platinum-based therapy (as noted 
below) and no more than 5 prior lines of systemic anticancer therapy in 
platinum-resistant disease (4 additional lines after the patient developed 
platinum-resistant/refractory disease). Patient must have received at least 1 line of 
therapy containing bevacizumab. The following guidelines apply: 
a. Patients who are primary platinum resistant (developed resistance after initial 
platinum-based therapy) must have received at least 4 cycles of platinum, must have 
had a response (CR or PR) and then progressed ≥3 to ≤6 months after the date of the 
last dose of platinum. 
b. Prior PARP inhibitor is allowed if included within these limits of prior therapy. Prior 
PARP inhibitor is required for patients with a BRCA mutation. 
c. Adjuvant ± neoadjuvant is considered 1 line of therapy. 


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d. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered part of 
the preceding line of therapy (ie, not counted independently). 
e. Therapy that changed due to toxicity in the absence of progression will be considered 
part of the same line (ie, not counted independently). 
f. Hormonal therapy will be counted as a separate line of therapy unless it was given as 
maintenance therapy. 
7. Patient has at least one measurable lesion that qualifies as a target lesion based on 
RECIST v1.1. Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are not considered measurable unless there has 
been demonstrated progression in the lesion. 
8. Patient is willing provide a tumor tissue sample either collected from a prior biopsy or 
cytoreductive/debulking surgery occurring at any time since diagnosis or from a fresh 
biopsy (newly obtained tumor tissue) at Screening. A tumor tissue sample collected at 
Screening (fresh biopsy) is preferred. Collection of tumor tissue samples from both prior 
biopsy or cytoreductive/debulking surgery and fresh biopsy are recommended (when 
possible) to understand changes in the tumor microenvironment during treatment. Central 
testing of PD-L1 status will be required prior to randomization. 
9. Patient has recovered from the effects of any previous chemotherapy, immunotherapy, 
other prior systemic anticancer therapy, radiotherapy, and/or surgery (ie, residual toxicity 
no worse than Grade 1 [Grade 2 treatment-associated peripheral neuropathy and/or any 
grade of alopecia are acceptable assuming all other inclusion criteria are met]). 
10. Patient who has received prior systemic anti-neoplastic agent(s) must wait at least 
5 half-lives or 4 weeks (whichever is shorter) following prior therapy before enrollment 
into the study or 4 weeks if the half-life of a given investigational agent is not known. 
11. Patient has an ECOG status of 0 or 1 and an estimated life expectancy of at least 
3 months. 
12. Patient has adequate hematologic reserve, as evidenced by: 
a. Absolute neutrophil count of ≥1,500/µL; 
b. Absolute lymphocyte count of ≥500/µL; 
c. Platelet count of ≥100,000/µL; and 
d. Hemoglobin of ≥9 g/dL (patient may be transfused to this level if necessary, but 
transfusion must occur >1 week prior to the first dose of study drug[s] and 
hemoglobin maintained to an acceptable level [≥9 g/dL] prior to first dose). 
Note: Administration of G-CSF or erythropoietin stimulating factor is permitted 
according to approved indications and scientific recommendations. Administration of 
long-acting G-CSF must occur >2 weeks prior to the first dose of study drug(s). 
Administration of short-acting G-CSF must occur >1 week prior to the first dose of 
study drug(s). 
13. Patient has adequate hepatic function, as evidenced by AST and ALT values ≤3 × the 
ULN and serum total bilirubin values of ≤1.5 × ULN (≤2 × ULN for patients with known 
Gilbert’s syndrome). For patients with documented baseline liver metastasis, the 
following limits will apply: ≤5 × ULN for ALT/AST and ≤2 × ULN for bilirubin. 


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14. Patient has adequate renal function, as evidenced by a calculated creatinine clearance of 
≥45 mL/min by the Cockcroft-Gault equation or a serum creatinine ≤1.5 × ULN. 
Creatinine clearance assessed by the Cockcroft-Gault equation is preferred over serum 
creatinine when assessing patient eligibility. 
15. Patient has INR and/or prothrombin time and aPTT ≤1.5 × ULN unless the patient is 
receiving anticoagulant therapy, in which case INR and/or prothrombin time and aPTT 
must be within the desired therapeutic range of intended use for such anticoagulants. 
16. Patient agrees to abide by the contraceptive requirements detailed in the protocol 
(Appendix 1). 
17. WOCBP must have a negative pregnancy test (serum or urine). (See Appendix 1 for the 
definition of WOCBP.) 
7.2. 
Patient Exclusion Criteria 
In order to qualify for participation in the study, patients must not meet any of the following 
criteria. Exclusion criteria should be assessed by the Investigator and, when applicable (per 
SOA) the assessment should occur within 10 days prior to expected C1D1 (closer to C1D1 is 
highly recommended). 
1. Patient has primary platinum-refractory disease or primary platinum resistance: primary 
platinum-refractory disease is defined as disease progression during initial 
platinum-based therapy; and primary platinum resistance is defined as disease 
progression <3 months after completion of initial platinum-based therapy. 
2. Patient has histologically confirmed diagnosis of EOC with mucinous or carcinosarcoma 
subtype. 
3. Patient has nonepithelial tumor (eg, germline or stromal cell tumor) or ovarian tumor 
with low malignant potential (ie, borderline or low-grade serous tumor). 
4. Patient requires recurrent (≥1 per month) fluid drainage (eg, paracentesis, thoracentesis, 
pericardiocentesis) or patient requires fluid drainage of ≥500 mL within 4 weeks of the 
expected date of the first dose of study drug. 
5. Patient has received prior IL-2-based or IL-15-based cytokine therapy; patient has had 
exposure, including intralesional, to IL-12 or analogs thereof. 
6. Patient has prior exposure to any anti-PD-1/PD-L1 therapy. 
7. Patient requires or has taken systemic corticosteroids (>10 mg of prednisone daily, or 
equivalent) within 14 days prior to the first dose of study drug(s); however, replacement 
doses, topical, ophthalmologic, and inhalational steroids are permitted. 
Note: patients requiring the use of a steroid during the Screening Period at a dose level of 
<10 mg of prednisone (or equivalent) per day are not excluded as long as the event 
requiring the use of the steroid has recovered to acceptable grade. 
8. Patient has taken nonsteroid systemic immunomodulatory agents (eg, etanercept, 
adalimumab, etc) within 28 days prior to the first dose of study drug(s), or anticipates any 
use of these therapies during the study period. 


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9. Patient has undergone any major surgical procedure within 3 weeks prior to Screening. 
Patients who have not recovered from any previous surgery that occurred more than 
3 weeks prior to Screening are also excluded. 
10. Patient has undergone prior solid organ and/or non-autologous hematopoietic stem cell or 
bone marrow transplant. 
11. Patient has received a live or live-attenuated vaccine(s) within 30 days prior to the first 
dose of study drug(s). Note: COVID-19 vaccine is allowed; see guidance on COVID-19 
vaccines in Section 7.3.2). 
12. Patient has had any active infection and/or a fever ≥38.5°C (≥101°F) within 7 days prior 
to the first dose of study drug(s) requiring systemic therapy. Antibiotics given for 
peri-procedural prophylaxis or given presumptively for a limited time (eg, until infection 
was ruled out), as well as topical or intraocular antibiotics, shall not be exclusionary. 
13. Patient has active autoimmune disease(s) requiring systemic treatment within the past 
2 years or a documented history of clinically severe autoimmune disease that has required 
chronic or frequent systemic steroids. Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is 
allowed. 
14. Patient has underlying chronic lung disease, chronic obstructive pulmonary disease, 
metastatic lung disease, pleural effusions, or other lung disorders (eg, pulmonary 
embolism) with a baseline room air oxygen saturation of <92% at Screening and/or 
dyspnea (≥Grade 3) which requires oxygen therapy. 
15. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis. 
16. Patient has any other concurrent uncontrolled illness or laboratory findings that may 
interfere with the planned treatment, affect patient compliance, such as recent serious 
trauma, or mental illness or substance use, which may interfere with the ability of the 
patient to cooperate and participate in the study. 
17. Patient is at high risk of treatment-related complications, such as: 
• Unstable, poorly controlled, or severe hypertension 
• Clinically significant pericardial effusion 
• New York Heart Association Class III or Class IV congestive heart failure 
(Appendix 2); high risk cardiovascular disease, defined as unstable angina. NOTE: If 
the Investigator plans to use PLD in the event the patient is randomized to Arm 4, 
patient has LVEF, as assessed by multiple gated acquisition scans or echocardiogram, 
below the institutional lower limit of normal. 
• Myocardial infarction, or cerebrovascular accident within 6 months of first dose of 
study drug(s) 
• Uncontrolled diabetes mellitus that has required 2 or more hospitalizations in the last 
year and/or emergent management within the last 6 months 


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• Severe peripheral vascular disease 
• A non-healing wound, ulcer, or bone fracture 
18. Patient has had an active second malignancy within the previous 2 years. This criterion 
does not apply to patients with adequately treated basal cell or squamous cell skin cancer, 
carcinoma in situ of the cervix, urothelial carcinoma in situ, or ductal carcinoma in situ of 
the breast that has undergone full surgical resection. 
19. Patient is currently pregnant, breastfeeding, or is planning to become pregnant or to begin 
breastfeeding during the study period or within 120 days after last study drug 
administration. 
20. Patient has active or symptomatic CNS metastases unless all the following have been 
met: such metastases have been treated by surgery and/or radiation therapy, and/or 
gamma knife and have remained radiographically stable (or shrinking) on 2 consecutive 
imaging examinations performed at least 6 weeks apart; and steroids have been tapered to 
a dose of 10 mg of prednisone (or equivalent) or less for at least 2 weeks prior to first 
dose of study drug(s); and the patient is neurologically stable. Patients with history of 
brain metastases or a suspicion of brain metastases must have a brain MRI at baseline. 
21. Patient has known or suspected hypersensitivity to pembrolizumab, nemvaleukin, PLD, 
paclitaxel, topotecan, gemcitabine, or to any of their excipients. 
Note: hypersensitivity to one or more of the chemotherapy choices is not exclusionary as 
long as the Investigator is able to select 1 of the 4 chemotherapy options for which the 
patient is known not to be hypersensitive.  
22. Patient has active uncontrolled coagulopathy. 
23. Patient has QT interval corrected by the Fridericia Correction Formula values of 
>470 msec; patient who is known to have congenital prolonged QT syndromes; or patient 
who is on medications known to cause prolonged QT interval on ECG. 
24. Patient is known to be positive for HIV. 
• For sites in Czech Republic only: patients test positive for HIV at Screening. 
25. Patients with known active hepatitis B (eg, HBsAg reactive) are excluded; however, a 
patient with past HBV infection or resolved HBV infection (defined as the presence of 
hepatitis B core antibody and absence of HBsAg) may be enrolled provided that HBV 
DNA is negative. Patients with known active hepatitis C (eg, HCV RNA [qualitative] are 
detected) are excluded; however, a patient with cured hepatitis C (negative HCV RNA 
status) may be enrolled.  
• For sites in Czech Republic only: patients test positive for HBV or HCV at Screening. 
26. History of bowel obstruction, history of abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within 3 months before the first dose of study drug is 
administered. Clinical symptoms of bowel obstruction should be ruled out by appropriate 
imaging studies during the Screening Period and prior to randomization in the study. 
Patients with a functioning ostomy can be included in the study. 


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27. Patients who are investigational site staff members directly involved in the conduct of the 
study or their immediate family members as well as site staff members otherwise 
supervised by the Investigator, or patients who are employed by Mural or 
companies/vendors hired to be directly involved in the conduct of the study (immediate 
family is defined as a spouse, parent, child, or sibling, whether biological or legally 
adopted) unless the investigational site staff or staff at Mural or companies/vendors 
working on behalf of Mural are recusing themselves from the study activities. 
7.3. 
Study Requirements and Restrictions 
7.3.1. 
Contraception and Pregnancy 
7.3.1.1. 
Patient Eligibility Requirements 
Patient agrees to abide by the contraception and egg donation requirements detailed in 
Section 7.3.1.2. 
A WOCBP must have a negative pregnancy test (urine or serum) performed by local laboratory 
within 3 days before the first dose of study drug is administered in every cycle. If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. If 
the serum pregnancy test is positive at Screening, the patient must be excluded from participation 
in the study. If the serum pregnancy test is positive prior to dosing in subsequent cycles, then the 
patient must be discontinued from study treatment (see Section 7.5.1). 
7.3.1.2. 
Contraception and Egg Donation Requirements During the Study 
All WOCBP must refrain from donating eggs and must practice sexual abstinence (as defined in 
Appendix 1) or use a contraceptive method that is highly effective (as described in Appendix 1) 
for the duration of the study and for at least 30 days (Arm 3) or 120 days (Arm 1, Arm 2) after 
the final dose of study drug. All heterosexually active WOCBP enrolled in Arm 4 (Investigator’s 
choice chemotherapy) must use contraceptive as per approved label and/or institutional 
guidelines for specific chemotherapy. 
7.3.1.3. 
If a Pregnancy Occurs 
If a patient becomes pregnant while participating in the study, she will be discontinued from 
study treatment immediately. The EOT and Safety Follow-up Visits will be scheduled, and a 
Pregnancy Report Form will be reported (Section 10.3.1.6) within 24 hours of awareness of the 
pregnancy, irrespective of whether an AE has occurred. Pregnancies that occur from the time of 
randomization through 120 days following last dose of study treatment or up to the start of new 
anticancer therapy, whichever is earlier, must be reported by the Investigator. The pregnancy will 
be followed until completion or termination. Additional follow-up may be required up to 
approximately the first year after the completion of the pregnancy. 
If the outcome of the pregnancy meets the criteria for classification as a SAE it should be 
reported following the SAE procedure (see Section 10.3.1.6). Note: Only SAEs that occur in 
study patients will be reported in the clinical database. 


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7.3.2. 
Concomitant and Prohibited Medications 
All intercurrent medical conditions will be treated at the discretion of the Investigator according 
to acceptable community standards of medical care. All concomitant medications and treatments 
will be documented on the eCRF. 
Any use of the following medications on study by patients is prohibited: 
• Any other investigational treatment. 
• Any other anti-neoplastic therapy including, but not limited to, cytotoxic 
chemotherapy, immunotherapy, any antibody therapy, other targeted agents, or 
hormonal therapy. 
• Radiotherapy, including systemically administered radioisotopes; however, limited 
field, palliative radiotherapy to a nontarget lesion at a site anatomically distinct from 
target lesion site(s) is allowed with notification to the Medical Monitor. 
• Immunomodulatory agents, including but not limited to interferons or ILs. 
• Live or live-attenuated vaccines within 30 days prior to the first dose of study drug, 
while participating in the study, and within 30 days after the last dose of study drug; 
however, inactivated vaccines are allowed.  
− For sites in Czech Republic only: live or live-attenuated vaccines within 30 days 
prior to the first dose of study drug, while participating in the study, and within 
90 days after the last dose of study drug; however, inactivated vaccines are 
allowed. 
• For Arms 1, 2, 3 only: Pharmacologic doses of systemic corticosteroids (>10 mg of 
prednisone daily, or equivalent); exception: systemic glucocorticoids are permitted 
only for the following purposes: 
− To modulate symptoms of an AE that is suspected to have an immunologic 
etiology (refer to Section 9.3.1). Note: study intervention interruption is required 
while the patient is receiving steroids >10 mg prednisone daily or equivalent. 
Restart of study intervention should be discussed with the medical monitor once 
steroid dose has been tapered to an acceptable dose level of ≤10 mg prednisone 
daily or equivalent. 
− As needed for the prevention of emesis 
− Premedication for IV contrast allergies 
− Short-term oral or IV use in doses >10 mg/day prednisone equivalent for chronic 
obstructive pulmonary disease exacerbations 
− For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent 
− In addition, the following glucocorticoid use is allowed: 
− For topical use or ocular use 
− Intra-articular joint use 


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− For inhalation in the management of asthma or chronic obstructive pulmonary 
disease 
• Surgery or radiotherapy for tumor control is not permitted during the study. 
COVID-19 vaccine is allowed (and if given, must be documented on the eCRF). At this time, the 
risks and benefits of COVID-19 vaccination in a cancer patient population are not completely 
understood. Generally, the benefits are felt to outweigh the risks. Guidance for administering the 
COVID-19 vaccine is provided below. As new data emerge, this guidance will be updated 
accordingly. 
• When administering, follow the full prescribing information of the vaccine. 
• When vaccine supplies are limited, administer to patients who are candidates for the 
vaccine in accordance with institutional, state, and national guidance and/or 
regulations. 
• There are no known drug-drug interactions between COVID-19 vaccines and 
nemvaleukin. 
• It is recommended that the vaccine is not administered within 7 days prior to or 
3 days after study drug administration; however, when needed this window can be as 
short as ±3 days. 
• Live-attenuated COVID-19 vaccine (if becomes available) should be avoided. 
Medroxyprogesterone or megestrol acetate may be given to patients as an appetite stimulant, and 
bisphosphonates or denosumab may be administered to patients with bone metastases if started at 
least 60 days before each respective patient’s first dose of study drug. 
As nemvaleukin is a protein, there are no anticipated metabolic drug-drug interactions. 
For patients being administered chemotherapy drugs (Arm 4), the relevant prescribing 
information should also be used for guidance on concomitant and prohibited medications. 
See Section 10.1.4 for details regarding the concomitant medication review. 
7.3.3. 
Meals and Dietary Restrictions 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 
7.4. 
Screen Failures 
Patients are screen failures if they cannot finish assessments for Screening or are ineligible based 
on those assessments. 


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7.5. 
Patient Discontinuation 
7.5.1. 
Patient Discontinuation From Treatment 
A patient will be discontinued from any of the study treatment at any time if the patient, 
Investigator, or Sponsor determines that it is not in the best interest of the patient to continue 
participation. Reasons for discontinuation from treatment include: 
• Radiological PD outlined in Section 10.2.1  
• Any progression or recurrence of malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 9.3.1 
• Withdrawal by patient (Note: All reasonable efforts should be made to encourage 
patients to remain on study for follow-up evaluations even if they withdraw from 
treatment) 
• Non-compliance with study schedule 
• Pregnancy 
• Physician decision 
• Study terminated by Sponsor 
• Lost to follow-up 
• Extraordinary site or healthcare related issues such as site closures due to COVID-19 
(See Appendix 5 for risk mitigation strategies related to the COVID-19 outbreak) 
For patients on combination therapy (Arm 1): patients who discontinue either nemvaleukin or 
pembrolizumab (eg, due to unacceptable toxicity that cannot be managed by dose modification) 
must discontinue all study treatment. Note: this does not apply to the discontinuation of 
pembrolizumab after 35 cycles (approximately 2 years). 
Patients who discontinue study treatment will be asked to continue with the EOT Visit, the 
30-day Safety Follow-up, and the Survival Follow-up as outlined in the SOA (Table 2 [Arms 1 
and 3], Table 3 [Arm 2], and Table 4 [Arm 4]). 
7.5.2. 
Patient Discontinuation From Study 
A patient will be discontinued from the study if any of the following occurs: 
• Withdrawal of consent by patient 
• Death 
• Lost to follow-up 
• Study terminated by Sponsor (See Appendix 5 for risk mitigation strategies related to 
the COVID-19 outbreak) 


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If a patient withdraws or is discontinued from the study for any reason, any ongoing AEs will be 
followed until resolution, until deemed stable by the Investigator, until death, or until the patient 
is deemed by the Investigator to be lost to follow-up. If, in the opinion of the Investigator, it is 
necessary to monitor a patient after the Follow-up Period has ended beyond the scheduled 
Survival Follow-up visits, the Follow-up Period may be extended as necessary. In such instances, 
the patient, Sponsor, and Investigator will agree to an acceptable follow-up schedule, while fully 
respecting the patient’s right to withdraw from the study at any time. 
In the event that a patient chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the patient’s 
rights. Patients who choose to withdraw from the study will be asked to return to the clinic for an 
EOT Visit. The EOT Visit should be scheduled within 7 days from the day the decision was 
made to discontinue study treatment. If the patient fails or refuses to return to the study center, an 
attempt must be made to contact the patient by telephone to assess as many safety and efficacy 
parameters as possible. All data collected over the telephone must be documented (in source 
documentation) and entered on the appropriate eCRF. 
The Investigator must maintain a record of all patients who fail to complete the study. The 
reason for study discontinuation will be documented and entered on the appropriate eCRF. If a 
patient is lost to follow-up, a reasonable attempt to contact the patient must be made and 
documented. If reasonable attempts to contact the patient or their family have failed, the Sponsor 
will request the study sites to collect survival status via available public records (Section 10.2.2). 
7.5.3. 
Minimizing Unnecessary Withdrawal 
In an effort to minimize the number of patients who are terminated from the study prior to study 
completion, the following procedures have been incorporated into the study design and study 
conduct: 
• Training of study centers on the importance of continued follow-up and on informed 
consent processes, and ensuring patients understand the commitment they are making, 
including intent to complete the study 
• Monitoring of data collection for adherence during the study 
Please see Section 11.3.4 for statistical considerations related to missing data. 
7.5.4. 
End of Study/Study Termination 
The end of the study is defined as the date of the last patient’s last visit (or, if applicable, the last 
phone call with the Investigator during the Follow-up Period) as indicated in the SOA. 
The Sponsor may terminate the entire study or a single study center at any time for safety, 
administrative, or other reasons. In the event of study or site termination, patients will be 
required to return for a final study assessment as close as possible to the patient’s last dose of 
study drug and will be advised by the Investigator regarding the available treatment options for 
the condition being studied. 


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Early study termination will occur if one or more of the following criteria are met: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to patients 
4. Plans to modify or discontinue the development of the study drug 
5. At the request of regulatory bodies (eg, IRB, FDA) 
In the event of Mural’s decision to no longer supply the study drug, sufficient notification will be 
provided so that appropriate adjustments to patient treatment can be made. 
7.6. 
Replacement of Patients 
Not applicable. 


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8. 
STUDY DESIGN 
8.1. 
Overall Study Design 
This is a Phase 3, multicenter, open-label, randomized study of nemvaleukin alfa in combination 
with pembrolizumab versus protocol-specific Investigator’s choice chemotherapy in patients 
with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. 
After signing the main ICF, candidate patients will attend a Screening Visit, at which eligibility 
will be assessed, and demographics, medical history, prior and concomitant medications, and 
prior procedures will be reviewed and recorded. If tumor tissue is to be collected for central 
testing of PD-L1 status prior to Screening, a pre-screening ICF will be obtained. For the 
purposes of confirming the diagnosis of EOC and for evaluating pretreatment tumor expression 
of genes and/or proteins of interest (eg, PD-L1 status, TMB, and microsatellite instability), an 
initial tumor biopsy will be obtained prior to the start of treatment, if such tissue is not already 
available. Archival tissue can be used in place of pretreatment biopsy. Central testing of PD-L1 
status will be required prior to randomization. 
Per the original study design, patients were centrally allocated in a randomized fashion (3:1:1:3) 
to receive either: 
• Arm 1: nemvaleukin and pembrolizumab combination therapy 
• Arm 2: pembrolizumab monotherapy (closed) 
• Arm 3: nemvaleukin monotherapy (closed) 
• Arm 4: Investigator’s choice chemotherapy. Options for protocol-specific 
Investigator’s choice chemotherapy include one of the following: PLD, paclitaxel, 
topotecan, or gemcitabine. The Investigator will pre-select the Investigator’s choice 
treatment before the randomization of each patient. 
The pembrolizumab monotherapy arm (Arm 2) met its pre-specified futility criteria at the 
planned futility analysis and was closed to enrollment as of 31 Aug 2023, per the 
recommendation of the IDMC. The nemvaleukin monotherapy arm (Arm 3) did not meet its 
pre-specified futility criteria at the planned futility analysis and the IDMC recommended 
continuation. Under protocol version 4.0, the nemvaleukin monotherapy Arm 3 reached its 
intended enrollment and thus closed. Because no changes have been made to the objectives to 
Arm 3 in protocol version 5.0, the Arm 3 number of patients was not recalculated. Therefore, in 
protocol version 5.0, eligible patients will continue to be enrolled in the remaining 2 arms and 
will be centrally allocated with a randomization ratio of 1:1 to the Combination and 
Chemotherapy arms (Arm 1 and Arm 4, respectively). 
To ensure equal distribution of prognostic factors in the study arms, patients will be stratified 
according to the following parameters: 
• PD-L1 status (IHC CPS ≥10 vs CPS <10) 
• Histological subtype (high-grade serous vs non-high-grade serous) 
• Investigator’s choice chemotherapy (paclitaxel vs other chemotherapies) 


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Response assessments will include CT scans and/or MRI every 6 weeks (Year 1) and every 
12 weeks (Year 2+), with mandatory imaging of chest, abdomen, and/or pelvis. Brain imaging at 
baseline (and during the study) should be performed when there is a history/suspicion of brain 
metastasis. Response and PFS will be evaluated per RECIST v1.1. For patients who complete 
treatment or discontinue treatment for reasons other than disease progression, every effort should 
be made to continue monitoring their disease status by radiologic imaging q6w (Year 1 from 
start of treatment) or q12w (Years 2+ from start of treatment) starting from the last on-treatment 
assessment until (1) the assessment of PD, (2) the initiation of new anticancer therapy(ies), 
(3) withdrawal of consent, (4) death, or (5) end of study, whichever occurs first. 
A schematic of the study design is provided in Figure 1. 
Figure 1: 
Study Design Schematic 
 
EOT=end of treatment, IV=intravenous, PLD=pegylated liposomal doxorubicin. 
Note: As of protocol version 5.0, the pembrolizumab and nemvaleukin monotherapy arms (Arm 2 and Arm 3, 
respectively) are closed to enrollment. 
*Treatment with pembrolizumab (Arms 1 and 2) is allowed for up to a maximum of 35 cycles (approximately 
2 years). 
**Alternatively, topotecan may be administered at 1.25 mg/m2 on Days 1 through 5 of 21-day cycles. 
8.2. 
Number of Patients Planned 
Approximately 376 patients were originally planned in a 3:1:1:3 ratio across 4 arms: 141 patients 
in Arm 1 (combination therapy), 47 patients in Arm 2 (pembrolizumab monotherapy), 
47 patients in Arm 3 (nemvaleukin monotherapy), and 141 patients in Arm 4 (Investigator’s 
choice chemotherapy).  
Under protocol version 5.0, approximately 450 patients are planned, including approximately 
366 patients planned across Arm 1 and Arm 4 (approximately 183 patients in each arm). Under 
protocol version 5.0, no additional patients will be enrolled in the pembrolizumab monotherapy 
or nemvaleukin monotherapy arms (Arm 2 and Arm 3, respectively). 
See Section 7.6 for the replacement of patients. 


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8.3. 
Duration of Treatment and Duration of Study 
Duration of treatment depends on the arm in which the patient is enrolled. Patients will receive 
treatment with nemvaleukin (Arms 1 and 3) for as long as they are experiencing disease control 
and are tolerating treatment well, or until any other criteria for treatment discontinuation are met. 
Treatment with pembrolizumab (Arms 1 and 2) will be allowed for up to a maximum of 
35 treatments (35 cycles; approximately 2 years). Patients in the nemvaleukin and 
pembrolizumab combination therapy (Arm 1) may continue nemvaleukin as monotherapy 
without pembrolizumab beyond 35 cycles upon discussion with the Sponsor and not meeting any 
other criteria for treatment discontinuation. 
Patients will receive chemotherapy (Arm 4) for as long as they are experiencing disease control 
and are tolerating treatment well, or until any other criteria for treatment discontinuation are met. 
The maximum duration of individual patient participation in the study is 3 years. Patients will be 
followed for survival for up to 3 years after initiation of treatment or until closure of study, 
whichever comes first. 


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9. 
STUDY DRUGS 
9.1. 
Administration of Study Drugs 
In this study, nemvaleukin and pembrolizumab are considered investigational study drugs. The 
options for chemotherapy (either PLD, paclitaxel, topotecan, or gemcitabine) are considered 
standard of care, non-investigational reference therapy drugs. Collectively, the investigational 
study drugs and reference therapy drugs will be described as study drugs. 
Sites must have written procedures in place detailing the healthcare personnel required to be 
on-site during patient dosing, the availability of equipment and medications necessary to treat an 
emergency (should it occur), and the process for transferring a patient to a medical facility if 
necessary. 
Descriptions and administration of study drugs are summarized in Table 7. Note: for 
protocol-specific chemotherapy agents, Institutional guidelines can be followed for duration of 
infusion to avoid or manage hypersensitivity reactions. 


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Table 7: 
Study Drug Description and Administration 
Intervention 
Name 
Nemvaleukin alfa 
Pembrolizumab 
PLD 
Paclitaxel 
Topotecan 
Gemcitabine 
Relevant Study 
Arms 
Arms 1, 3 
Arms 1, 2 
Arm 4 
Arm 4 
Arm 4 
Arm 4 
Type  
Biologic 
Biologic 
Drug 
Drug 
Drug 
Drug 
Dosage Level(s) 
6 µg/kg/day;  
Days 1 through 
5 of 21-day cycles 
200 mg;  
Day 1 of 21-day 
cycles 
40 mg/m2;  
Day 1 of 28-day 
cycles 
80 mg/m2;  
Days 1, 8, 15, and 
22 of 28-day 
cycles 
4 mg/m2;  
Days 1, 8, and 15 
of 28-day cycles; 
or 1.25 mg/m2, 
Days 1 through 5 
of 21-day cycles 
1,000 mg/m2;  
Days 1 and 8 of 
21-day cycles 
Route of 
Administration 
IV infusion over 
30 min 
IV infusion over 
30 min 
IV infusion; 
1 mg/min 
(Cycle 1); 60-min 
infusion (Cycles 
2+) 
IV infusion over 
60 min 
IV infusion over 
30 min 
IV infusion over 
30 min 
Sourcing 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Provided locally 
by the study site, 
subsidiary, or 
designee 
Provided locally 
by the study site, 
subsidiary, or 
designee 
Provided locally 
by the study site, 
subsidiary, or 
designee 
Provided locally 
by the study site, 
subsidiary, or 
designee 
Packaging and 
Labeling 
Study Intervention 
will be provided in 
single-dose vials 
of lyophilized 
powder 
Study Intervention 
will be provided in 
single-dose vials of 
either lyophilized 
powder or solution 
NA  
NA 
NA 
NA 
IV=intravenous, NA=not applicable, PLD=pegylated liposomal doxorubicin. 


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Nemvaleukin drug product is supplied at a concentration of 1 mg/mL in a single-dose vial of 
lyophilized powder. Patients receiving nemvaleukin will be administered nemvaleukin at 
6 µg/kg/day for 5 consecutive days, q21d, via a 30-minute IV infusion (refer to Pharmacy 
Manual). A mandatory 2-hour observation period, to commence after the completion of infusion, 
may be extended as recommended in Section 9.2.1. 
Pembrolizumab is supplied as single-dose vials of either lyophilized powder or solution. Patients 
receiving pembrolizumab will be administered pembrolizumab at 200 mg q21d via a 30-minute 
IV infusion. Nemvaleukin and/or pembrolizumab may be infused using peripheral or central 
venous access per local standards of care and the treating Investigator’s judgment. All patients 
should have adequate IV access to allow the immediate management of toxicities. Patients who 
do not have adequate peripheral venous access should have a central venous access device placed 
per local standards of care. 
For patients randomized to Arm 1, nemvaleukin will be administered prior to pembrolizumab, 
with a 30-minute observation period between infusions. The mandatory 2-hour post-infusion 
observation period shall commence after the completion of pembrolizumab infusion. 
Investigator’s choice chemotherapy will be sourced per institution and documented accordingly 
in eCRF. Single-agent chemotherapy must be selected prior to randomization; choice of 
chemotherapy is not allowed to be changed during the course of the study. 
Sites should make every effort to target infusion timing to be as close to the indicated duration as 
possible (ie, 30 or 60 minutes). However, given the variability of infusion pumps from site to 
site, a window between −5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes 
[−5 minutes/+10 minutes] or 60 minutes [−5 minutes/+10 minutes]). 
9.2. 
Guidance for Study Drug Administration 
9.2.1. 
Guidance for Nemvaleukin Administration 
• Administration of antipyretics is recommended prior to nemvaleukin administration, 
during dosing of nemvaleukin, and subsequently as needed. Premedications such as 
antihistamines, nonsteroidal anti-inflammatory agents, H2-blockers, and/or other 
agents may also be used per the Investigator’s discretion. 
• Prophylactic use of systemic corticosteroids is not allowed. 
• Post-administration prophylactic use of antipyretics, nonsteroidal anti-inflammatory 
drugs, and/or H2-blockers may be utilized per institutional guidelines and may be 
administered starting 4 to 6 hours following nemvaleukin administration, per the 
Investigator’s discretion. 
• All premedications and postdose medications (those prescribed prophylactically) 
must be captured in the appropriate eCRFs with reason for use being “prophylaxis.” 
• It is recommended that patients be well hydrated (orally or with IV fluids) and not 
fasting for long periods (>4 hours) prior to nemvaleukin administration. 


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• For patients who have had or are at risk of experiencing hypotension following 
nemvaleukin alfa administration, consider withholding antihypertensive medications 
24 to 48 hours prior to the next dose of nemvaleukin, per Investigator discretion. For 
patients receiving nemvaleukin and who have had or are at risk of experiencing 
hypotension, avoid H1-blockers as premedication if possible and monitor the patient 
for a longer duration (recommended up to 6 hours), per the Investigator’s discretion. 
• Demerol (meperidine) may be administered to patients who experience intolerable 
chills. 
• Montelukast leukotriene receptor antagonists may be administered to patients as a 
pre-medication to help reduce symptoms of CRS, especially for patients who have a 
history of sensitivity to other systemic agents. 
• For patients who experience nemvaleukin-related toxicity, refer to Section 9.3.1.1 for 
additional guidance prior to resuming dosing. 
• For the impact of the investigational drug as it relates to COVID 19, refer to 
Appendix 5. 
9.2.2. 
Guidance for Pembrolizumab Administration 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator. 
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the pembrolizumab dose modification guidelines in 
Section 9.3.1.2. 
9.2.3. 
Guidance for Chemotherapy Administration 
Hypersensitivity premedication should be administered in accordance with local standard of care 
in order to prevent severe hypersensitivity reactions. Institutional guidelines can be followed for 
duration of infusion to avoid or manage the hypersensitivity reactions.  
Administration of growth factors (eg, G-CSF, erythropoietic growth factor) or blood transfusion 
is permitted according to approved indications and scientific recommendations. All 
pre-medications and postdose medications (those prescribed prophylactically) must be captured 
in the appropriate eCRFs with reason for use being “prophylaxis”. 
For all toxicities, patients should receive appropriate management and/or supportive care 
measures as deemed necessary by the treating Investigator. For patients who experience 
chemotherapy-related toxicity, refer to Section 9.3.1 for guidance prior to resuming dosing. 
9.3. 
Study Drug Adjustments, Stopping Rules, and Dose Delays 
9.3.1. 
Dosing Modification and Management of Toxicities 
For all toxicities, optimal supportive care is recommended before considering dose modification 
of study drug(s). All dose reductions, interruptions (dose skipping or delay), re-challenges, and 
treatment discontinuations of study drug(s) due to AEs/SAEs should be discussed with the 
Medical Monitor and must be recorded on the eCRF with their corresponding AE/SAE following 


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eCRF completion guidelines. Please refer to Section 10.3.1.2 for complete clinical definitions of 
AESIs. 
If discontinuing study drug(s) permanently, the patient should still be followed for safety and 
PFS/OS. 
The weight measurements performed at the Day 1 Visit of each cycle should be considered for 
dose adjustments. The dose of nemvaleukin should be adjusted if the patient’s weight changes by 
>10% since the last time the dose was calculated or adjusted. Weight-based dose adjustments are 
not applicable to pembrolizumab. Prescribing information or local institutional guidelines, if 
available, should be followed for weight-based dose adjustments during administration of 
chemotherapies. 
9.3.1.1. 
Nemvaleukin: Dosing Modification and Management of Toxicities 
There is no allowance for an extension of the 5-(consecutive) day treatment period within each 
cycle. If a patient misses dosing for any reason on a scheduled day within the 5-day treatment 
period (eg, Day 2, Day 3, or Day 4), then the patient may continue with dosing on the next 
scheduled day; the missed day is not to be replaced. Thus, the 5-day treatment period is 
unchanged. If the patient misses the fifth dosing day in a cycle, then the next scheduled dosing 
day will be Day 1 of the following cycle. If the patient misses dosing on the scheduled first day 
of dosing in a cycle, the next available dosing day will be considered Day 1. Note: for patients 
receiving nemvaleukin and pembrolizumab combination therapy, pembrolizumab is not to be 
administered if the patient misses nemvaleukin dosing on the scheduled first day of dosing in a 
cycle. 
Dosing modifications may be required to manage toxicity. For recommendations on nemvaleukin 
dose modifications for the management of nemvaleukin-related toxicities, refer to Table 8 
(excludes AESIs) and Table 9 (AESIs). Any laboratory value that meets any criteria for dosing 
modifications should be confirmed with a second test. For any asymptomatic laboratory value 
changes that are known to be a transient effect of IL-2 class drugs (eg, AST/ALT elevations, 
neutrophil count decrease), the dose modification could be delayed; refer to Table 8. Dose 
reductions will be allowed from 6 µg/kg/day to 3 µg/kg/day; no further dose reductions are 
allowed. 
Patients who discontinue either nemvaleukin or pembrolizumab due to unacceptable toxicity that 
cannot be managed by dose modification must discontinue both study treatments. Patients who 
require treatment hold for either nemvaleukin or pembrolizumab due to unacceptable toxicity, 
based on recommendation in Table 9, may hold both study treatments. However, holding one 
agent is feasible if the Investigator’s causality assessment clearly attributes the AE to only one of 
the components. 


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Table 8: 
Recommendations for Nemvaleukin Dosing Modifications for Drug-Related Toxicity (Excluding Adverse Events 
of Special Interest) 
Toxicity 
Grade 
Temporarily 
Hold 
Treatment 
Timing for 
Resuming 
Treatment 
Dose/Schedule for Resuming 
Treatment 
Discontinue Study Drug  
Hematologic 
(excluding 
uncomplicated 
G3 neutropenia, 
lymphopenia) 
3 to 4 
Yes 
Toxicity 
resolves to G1 
or less 
If toxicity resolves in ≤3 weeks, resume 
same dose and schedule 
If toxicity resolves in >3 to <6 weeks, 
or in patient with recurrent G3 to G4 
events, reduce dose as follows: 
• 
reduce dose to 3 µg/kg/day 
If toxicity does not resolve to lower grade in ≥6 weeks 
of dose hold, consider permanent discontinuation 
If patient experiences recurrent G3 to G4 toxicity after 
nemvaleukin administration (at any dose), consider 
permanent discontinuation 
Non-
Hematologic 
(excluding 
alopecia) 
3 
Yes 
Toxicity 
resolves to G1 
or less 
If toxicity resolves in ≤3 weeks, resume 
same dose and schedule 
If toxicity resolves in >3 to <6 weeks, 
or in patient with recurrent G3 events, 
reduce dose as follows: 
• 
reduce dose to 3 µg/kg/day 
If toxicity does not resolve to lower grade in ≥6 weeks 
of dose hold, consider permanent discontinuation 
If G3 toxicity recurs at reduced dose, or patient 
experiences recurrent G3 toxicity after nemvaleukin 
administration (at any dose), consider permanent 
discontinuation 
4a 
Yes 
Toxicity 
resolves to G1 
or less 
Consult with Medical Monitor to 
determine if appropriate to continue 
nemvaleukin with dose reduction as 
follows: 
• 
reduce dose to 3 µg/kg/day 
Consider permanent discontinuation 
If patient experiences recurrent G4 toxicity, 
permanently discontinue 
G=Grade. 
a For sites in France only: patients should permanently discontinue nemvaleukin if a Grade 4 non-hematologic toxicity occurs. 


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Table 9: 
Recommendations for Nemvaleukin Dosing Modifications for Drug-Related Adverse Events of Special Interest 
Toxicitya 
Grade 
Temporarily 
Hold 
Treatment 
Timing for 
Resuming 
Treatment 
Dose/Schedule for Resuming 
Treatment 
Discontinue Study Drug  
IRR/CRS 
3 
Yes 
Toxicity resolves to 
G1 or less 
Resume with same dose with 
premedicationsb in setting where 
emergent care is available 
If G3 toxicity recurs, resume with 
reduced dose with premedicationsb in 
setting where emergent care is available 
Dose reduction is as follows: 
• 
reduce dose to 3 µg/kg/day 
If G3 toxicity recurs at reduced dose, 
permanently discontinue 
4 
Yes 
NA 
NA 
Permanently discontinue 
CLS 
2 
Yes 
Toxicity resolves to 
G1 or less 
Resume with reduced dose with 
premedicationsb in setting where 
emergent care is available 
Dose reduction is as follows: 
• 
reduce dose to 3 µg/kg/day 
Consider permanent discontinuation 
Consult with Medical Monitor to 
determine if appropriate to continue 
nemvaleukin with dose reduction 
If G2 toxicity recurs at reduced dose, 
permanently discontinue 
3 to 4 
Yes 
NA 
NA 
Permanently discontinue 
irAE of 
pneumonitis, 
nephritis or 
relevant labs 
undergoing 
work-up for 
irAE of nephritis 
2 
Yes 
Toxicity resolves to 
G1 or less 
Resume with reduced dose as follows: 
• 
reduce dose to 3 µg/kg/day 
If G2 toxicity recurs at reduced dose, 
permanently discontinue 
3 to 4 
Yes 
NA 
NA 
Permanently discontinue 
irAE of colitis 
2 to 3 
Yes 
Toxicity resolves to 
G1 or less 
Resume with reduced dose as follows: 
• 
reduce dose to 3 µg/kg/day 
If G2 to G3 toxicity recurs at reduced 
dose, permanently discontinue 
4 
Yes 
NA 
NA 
Permanently discontinue 


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Toxicitya 
Grade 
Temporarily 
Hold 
Treatment 
Timing for 
Resuming 
Treatment 
Dose/Schedule for Resuming 
Treatment 
Discontinue Study Drug  
irAE of 
endocrinopathies 
3 
Yes 
Toxicity resolves to 
G1 or less and/or 
controlled with 
adequate 
replacement 
Resume with same dose 
If G3 toxicity recurs, reduce dose as 
follows: 
• 
reduce dose to 3 µg/kg/day 
If G3 toxicity recurs at reduced dose, 
permanently discontinue (excluding 
endocrinopathies that can be controlled 
with hormone replacement therapy) 
4 
Yes 
NA 
NA 
Permanently discontinue (excluding 
endocrinopathies that can be controlled 
with hormone replacement therapy) 
irAE of hepatitis 
or relevant labs 
undergoing 
workup for 
irAE of hepatitis 
2c 
Yes 
Toxicity resolves to 
G1 or less 
If toxicity resolves to G1 in <2 weeks, 
resume at same dose 
If toxicity resolves in >2 weeks, discuss 
with Medical Monitor or designee 
If dose reduction is required, resume 
with reduced dose as follows: 
• 
reduce dose to 3µg/kg/day 
If G2 toxicity recurs at reduced dose, 
permanently discontinue 
3d 
Yes 
After discussion with 
Medical Monitor 
Discuss with Medical Monitor or 
designee 
For nemvaleukin-related asymptomatic 
G3 lab event, discuss with Medical 
Monitor prior to discontinuing 
4e  
Yes 
NA 
NA 
Permanently discontinue 
irAE of 
neurological 
toxicities 
2 
Yes 
Toxicity resolves to 
G1 or less 
Resume with reduced dose as follows: 
• 
reduce dose to 3 µg/kg/day 
If G2 toxicity recurs at reduced dose, 
permanently discontinue 
3 to 4 
Yes 
NA 
NA 
Permanently discontinue 
Myocarditis 
2 to 4 
Yes 
NA 
NA 
Permanently discontinue 
Exfoliative 
dermatologic 
conditions 
Suspected SJS, 
TEN, or 
DRESS of any 
grade  
Yes 
Toxicity resolves to 
G0 
Resume with reduced dose as follows: 
• 
reduce dose to 3 µg/kg/day 
after consultation with Medical 
Monitor 
If toxicity recurs at reduced dose, 
permanently discontinue 
Confirmed SJS, 
TEN, or 
Yes 
NA 
NA 
Permanently discontinue 


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Toxicitya 
Grade 
Temporarily 
Hold 
Treatment 
Timing for 
Resuming 
Treatment 
Dose/Schedule for Resuming 
Treatment 
Discontinue Study Drug  
DRESS of any 
grade 
All other irAE 
2 (persistent) 
Yes 
Toxicity resolves to 
G1 or less 
Resume with same dose 
If ≥G2 toxicity recurs, reduce dose as 
follows: 
• 
reduce dose to 3 µg/kg/day 
If G2 toxicity recurs at reduced dose, 
permanently discontinue 
3 (recurrent), or 
4 (anytime) 
Yes 
NA 
NA 
Permanently discontinue 
AESI=adverse event of special interest, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CLS=capillary leak syndrome, CRS=cytokine release 
syndrome, DRESS=Drug Rash with Eosinophilia and Systemic Symptom, G=Grade, irAE=immune-related adverse event, IRR=infusion-related reaction, 
NA=not applicable, SJS=Stevens-Johnson Syndrome, TEN=Toxic Epidermal Necrolysis, ULN=upper limit of normal. 
a Refer to Section 10.3.1.2 for complete clinical definitions of the AESIs. 
b Refer to Section 9.2.1 for guidance on premedication for nemvaleukin. 
c AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 
3.0 × baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 
10.0 × baseline if baseline abnormal. 
e AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal; bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline 
abnormal. 


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9.3.1.2. 
Pembrolizumab: Dosing Modification and Management of Toxicities 
Dose adjustments of pembrolizumab are not allowed. The IB for pembrolizumab should be 
followed for toxicity management, including dosing modifications to manage 
pembrolizumab-related toxicities. 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks (21 days) of the originally 
scheduled dose and within 42 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for study intervention interruption is to be documented in 
the patient’s study record. 
Dose Modification and Toxicity Management for Immune-related AEs Associated With 
Pembrolizumab 
Adverse events associated with pembrolizumab exposure may represent an immune-related 
response. These irAEs may occur shortly after the first dose or several months after the last dose 
of pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, and/or skin biopsy may be 
included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab monotherapy or immuno-oncology combination are provided in Table 10. 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Pembrolizumab Monotherapy or Immuno-Oncology Combinations 
General instructions: 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤10 mg/day within 12 weeks of the last treatment. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
• Add prophylactic antibiotics 
for opportunistic infections 
• Monitor patients for signs and symptoms of 
pneumonitis 
• Evaluate patients with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment 
Recurrent Grade 2, 
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
• Monitor patients for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus) 
• Patients with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis 
• Patients with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion 
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Pembrolizumab Monotherapy or Immuno-Oncology Combinations (Continued) 
General instructions: 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤10 mg/day within 12 weeks of the last treatment. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other Therapies 
Monitoring and Follow-up 
AST or ALT 
Elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
• Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
• Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
• Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglycemia 
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold d 
• Initiate insulin replacement therapy for 
patients with T1DM 
• Administer antihyperglycemic in patients 
with hyperglycemia 
• Monitor patients for hyperglycemia 
or other signs and symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
• Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Pembrolizumab Monotherapy or Immuno-Oncology Combinations (Continued) 
General instructions: 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤10 mg/day within 12 weeks of the last treatment. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
• Monitor for signs and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care 
• Monitor for signs and symptoms of 
thyroid disorders 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
• Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
• Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 or 4 
Permanently 
discontinue 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Pembrolizumab Monotherapy or Immuno-Oncology Combinations (Continued) 
General instructions: 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤10 mg/day within 12 weeks of the last treatment. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Myocarditis 
Asymptomatic cardiac 
enzyme elevation with 
clinical suspicion of 
myocarditis (which was 
previously myocarditis 
Grade 1 using 
CTCAE v4.0) 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 2, 3, or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN, or 
DRESS 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed SJS, TEN, 
or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based on 
the event e  
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 


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AE(s)=adverse event(s), ALT=alanine aminotransferase, AST=aspartate aminotransferase, CTCAE=Common Terminology Criteria for Adverse Events, 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom, GI=gastrointestinal, IO=immuno-oncology, ir=immune-related, IV=intravenous, 
SJS=Stevens-Johnson Syndrome, T1DM=type 1 diabetes mellitus, TEN=Toxic Epidermal Necrolysis, ULN=upper limit of normal. 
a AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal;  
bilirubin: >1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal. 
b AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal;  
bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline if baseline abnormal. 
c AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal;  
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal. 
d The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the Investigator or 
treating physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 


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Dose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in the Pembrolizumab IB. 
9.3.1.3. 
PLD: Dosing Modification and Management of Toxicities 
Up to 2 dose reductions are acceptable for PLD (Table 11). Guidance for PLD dosing 
modifications is provided in Table 12 and Table 13. The study site can apply institutional 
guidance if available. 
Table 11: 
Dose Reduction Levels of Pegylated Liposomal Doxorubicin 
 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
40 mg/m2 
30 mg/m2 
20 mg/m2 


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Table 12: 
Guidance for Pegylated Liposomal Doxorubicin Dosing Modifications 
ANC=absolute neutrophil count, G-CSF=granulocyte colony-stimulating factor, LVEF=left ventricular ejection 
fraction, NA=not applicable, PLD=pegylated liposomal doxorubicin. 
Toxicity 
Temporarily 
Hold 
Treatment 
Timing for 
Resuming 
Treatment 
Dose/ Schedule 
for Next 
Treatment 
Discontinue Study Drug  
Hematologic 
Grade 4 neutropenia 
≥7 days, or 
All other Grade 4 
hematological toxicity, or 
febrile neutropenia, or 
cycle delay for 
hematological toxicity or 
thrombocytopenic bleeding 
Yes 
ANC 
≥1.5 × 109/L and 
platelet 
≥100 × 109/L 
If toxicity 
resolves in 
<6 weeks, 
decrease dose by 
1 level, or 
continue with the 
same dose as 
previously 
administered with 
G-CSF support 
-If toxicity does not resolve 
to lower grade in ≥6 weeks 
of dose hold, consider 
permanent discontinuation 
-If Grade 3 to 4 events recur 
at lowest reduced dose, 
consider permanent 
discontinuation 
15% change from baseline 
in LVEF, or below normal 
NA 
NA 
NA 
Permanently discontinue 
Non-Hematologic 
All major organ Grade 3 
toxicity that is not 
disease-related (excluding 
alopecia, nausea, or 
vomiting) at start of next 
cycle 
For mucositis & cutaneous 
toxicity, see Table 13  
Yes 
When the 
toxicity is no 
longer clinically 
significant per 
Investigator’s 
discretion 
If resolve to 
lower grade in 
<6 weeks, 
decease dose by 
1 level 
-If toxicity does not resolve 
to lower grade in ≥6 weeks 
of dose hold, consider 
permanent discontinuation. 
-If Grade 3 events recur at 
lowest reduced dose, 
consider permanent 
discontinuation. 
All major organ Grade 4 
toxicity that is not 
disease-related (excluding 
mucositis & cutaneous 
toxicity) 
For mucositis & cutaneous 
toxicity, see Table 13 
NA 
NA 
NA 
Permanently discontinue 
Hypersensitivity reaction 
to PLD, all grades 
Stop infusion 
immediately; 
symptomatic 
therapy should 
be initiated 
Once reaction is 
completely 
resolved 
For Grade 1 to 2 
hypersensitivity 
reactions, 
consider 
rechallenge with 
premedications 
and at a reduced 
rate 
-If Grade 3 to 4 
hypersensitivity reactions 
occur, permanently 
discontinue; the patient 
should not be re-challenged. 
-If Grade 1 to 2 reactions 
occurring with 
premedications and at lowest 
reduced dose, consider 
permanent discontinuation 


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Table 13: 
Summary of Pegylated Liposomal Doxorubicin Dose Reductions in Case of 
Mucositis and Cutaneous Toxicity 
NA=not applicable, PLD=pegylated liposomal doxorubicin. 
9.3.1.4. 
Paclitaxel: Dosing Modification and Management of Toxicities 
Up to 2 dose reductions are acceptable for paclitaxel (Table 14). If dose is reduced to 70 mg/m2 
and followed by an omission of the next dose within a treatment cycle, 70 mg/m2 can be 
maintained in lieu of a second dose reduction. Guidance for paclitaxel dosing modifications is 
provided in Table 15. The study site can apply institutional guidance if available. 
Table 14: 
Dose Reduction Levels of Paclitaxel 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
80 mg/m2 
70 mg/m2 
60 mg/m2 
 
Grade  Mucositis  
Cutaneous  
Situation at Day 28  
Situation at 
Day 35  
Situation at 
Day 42  
1  
Painless ulcers, 
erythema, or 
mild soreness  
Mild erythema, 
swelling, or 
desquamation not 
interfering with daily 
activities  
Wait an additional 
week and re-dose at 
full dose unless 
patient had 
experienced a Grade 
>2 toxicity in which 
case reduce dose by 
1 level  
Wait an additional 
week and reduce 
dose by 1 level  
Permanently 
discontinue 
PLD 
2  
Painful 
erythema, 
edema, or 
ulcers, but can 
eat 
Erythema, 
desquamation, or 
swelling interfering 
with but not 
precluding normal 
activities; can wear 
regular cloth 
Wait an additional 
week and reduce 
dose by 1 level 
Wait an additional 
week and reduce 
dose by 1 level in 
case of first 
occurrence, or 
permanently 
discontinue PLD 
Permanently 
discontinue 
PLD 
3  
Painful 
erythema, 
edema, or 
ulcers, and 
cannot eat  
Blisters, ulceration, 
or swelling 
interfering with 
walking or normal 
daily activities; 
cannot wear regular 
cloth  
Wait an additional 
week and reduce 
dose by 1 level in 
case of first 
occurrence or 
Discontinue PLD  
Discontinue PLD  
Permanently 
discontinue 
PLD 
4  
Requires 
parenteral or 
enteral support  
Diffuse or local 
process causing 
infectious 
complications, or a 
bedridden state or 
hospitalization  
Discontinue PLD  
Discontinue PLD  
Permanently 
discontinue 
PLD 


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Table 15: 
Guidance for Paclitaxel Dosing Modifications 
Toxicity 
Temporarily Hold 
Treatment 
Timing for Resuming 
Treatment 
Dose/Schedule for Next 
Treatment 
Discontinue Study Drug  
Hematologic 
ANC <1.5 × 109/L and/or 
platelets <100 × 109/L at start 
of each cycle 
Yes 
ANC ≥1.5 × 109/L and 
platelets ≥100 × 109/L 
within 6 weeks of last 
dosea 
No change. Consider 
prophylactic G-CSF 
support 
-If toxicity does not resolve to lower 
grade in ≥6 weeks of dose hold, consider 
permanent discontinuation 
-For recurrent Grade 3 to 4 events, 
consider permanent discontinuation 
ANC ≤0.5 × 109/L and/or 
platelets ≤75 × 109/L  
Yes 
ANC ≥1.5 × 109/L and 
platelet ≥100 × 109/L 
within 6 weeks of last 
dosea 
Decease dose by 1 level. 
Consider prophylactic 
G-CSF support 
-If toxicity does not resolve to lower 
grade in ≥6 weeks of dose hold, consider 
permanent discontinuation 
-For recurrent Grade 3 to 4 events, 
consider permanent discontinuation 
Non-Hematologic 
All major organ Grade 3 
toxicity that is not disease-
related, excluding alopecia, 
nausea, or vomiting 
Yes 
When the toxicity is no 
longer clinically 
significant per 
Investigator’s discretion 
within 6 weeks of last 
dose 
Decrease dose by 1 level -If toxicity does not resolve to lower 
grade in ≥6 weeks of dose hold, consider 
permanent discontinuation 
-If Grade 3 event recurs at lowest reduce 
dose, consider permanent discontinuation 
All major organ Grade 4 
toxicity that is not 
disease-related  
NA 
NA 
NA 
Permanently discontinue 
Hypersensitivity reaction  
Stop infusion immediately; 
symptomatic therapy should 
be initiated  
When the toxicity is no 
longer clinically 
significant per 
Investigator’s discretion 
For Grades 1 to 2 
hypersensitivity 
reactions, consider 
rechallenge with 
premedications and at a 
reduced rate 
-If Grade 3 to 4 hypersensitivity reactions 
occur, permanently discontinue; the 
patient should not be re-challenged 
-For recurrent Grade 1 to 2 reactions 
occurring with premedications, consider 
permanent discontinuation 
ANC=absolute neutrophil count, G-CSF=granulocyte colony-stimulating factor, NA=not applicable. 
a For patients who do not achieve hematological recovery on scheduled day of the course, complete blood counts should be performed twice weekly until the 
above defined limits are achieved. 


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9.3.1.5. 
Topotecan: Dosing Modification and Management of Toxicities 
Up to 2 dose reductions are acceptable for topotecan weekly dosing (Table 16). Dose escalation 
is not permitted. Guidance for topotecan dosing modifications is provided in Table 17. The study 
site can apply institutional guidance if available. 
Table 16: 
Dose Reduction Levels of Topotecan 
Dosing Schedule 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Weekly Dosing 
4 mg/m2 
3.5 mg/m2 
3 mg/m2 
5-day Dosing 
1.25 mg/m2 
1.0 mg/m2 
0.75 mg/m2 
 


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Table 17: 
Guidance for Topotecan Dosing Modifications (Weekly and 5-Day Dosing Schedules) 
Toxicity 
Temporarily 
Hold 
Treatment 
Timing for Resuming Treatment 
Dose/ Schedule for Next 
Treatment 
Discontinue Study Drug  
Hematologic 
Grade 4 neutropenia ≥7 days, 
or 
All other Grade 4 
hematological toxicity, or 
febrile neutropenia, or 
Cycle delay for hematological 
toxicity, or 
Thrombocytopenic bleeding 
Yes 
When neutrophils ≥1,000/μL,  
Hb ≥9 g/dL, and platelets 
≥80,000/μL (weekly dosing) or 
platelets ≥100,000/μL (5-day 
dosing)  
If toxicity resolves in <6 weeks, 
decrease dose by 1 level or 
continue with the same dose as 
previously administered with 
G-CSF support 
If toxicity recurs with 
prophylactic G-CSF support, 
reduce 1 dose level 
For Grade 4 thrombocytopenia, 
reduce 1 dose level  
-If toxicity does not resolve to lower 
grade in ≥6 weeks of dose hold, 
consider permanent discontinuation 
-If Grade 3 to 4 events recur at 
lowest reduced dose, consider 
permanent discontinuation 
Non-Hematologic  
Grade 2 neurotoxicity, or 
All major organ Grade 3 
toxicity that is not 
disease-related (excluding 
alopecia, nausea, or vomiting) 
Yes 
When the toxicity is no longer 
clinically significant per 
Investigator’s discretion 
If toxicity resolves in <6 weeks, 
decease dose by 1 level 
-If toxicity does not resolve to lower 
grade in ≥6 weeks of dose hold, 
consider permanent discontinuation 
-If Grade 3 events recur at lowest 
reduced dose, consider permanent 
discontinuation 
All major organ Grade 4 
toxicity that is not 
disease-related, or 
Pneumonitis (confirmed) of 
any grade 
NA 
NA 
NA 
Permanently discontinue 
G-CSF=granulocyte colony-stimulating factor, Hb=hemoglobin, NA=not applicable. 
 


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9.3.1.6. 
Gemcitabine: Dosing Modification and Management of Toxicities 
Up to 2 dose reductions are acceptable for gemcitabine (Table 18). Guidance for gemcitabine 
dosing modifications is provided in Table 19. The study site can apply institutional guidance if 
available. 
Table 18: 
Dose Reduction Levels of Gemcitabine 
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
1,000 mg/m2 
750 mg/m2 
500 mg/m2 
 


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Table 19: 
Guidance for Gemcitabine Dosing Modifications 
Toxicity 
Temporarily 
Hold 
Treatment 
Timing for Resuming 
Treatment 
Dose/Schedule for Next 
Treatment 
Discontinue Study Drug  
Hematologic 
ANC <1.5 × 109/L, platelets 
<100 × 109/L, or 
febrile neutropenia, or 
thrombocytopenic bleeding 
Yes 
ANC ≥1.5 × 109/L and 
platelet ≥100 × 109/L 
If toxicity resolves to a 
lower grade within 
<6 weeks of dose hold, 
restart treatment with dose 
reduced by 1 level; or 
continue with the same 
dose as previously 
administered, with G-CSF 
support 
-If toxicity does not resolve to lower 
grade within ≥6 weeks of dose hold, 
consider permanent discontinuation 
-If Grade 3 to 4 events recur at lowest 
reduced dose, consider permanent 
discontinuation 
Non-Hematologic 
All major organ Grade 3 to 4 
toxicity that is not 
disease-related (excluding 
alopecia, nausea, or vomiting) 
Yes 
When the toxicity is no longer 
clinically significant per 
Investigator’s discretion 
If toxicity resolves to a 
lower grade within 
<6 weeks of dose hold, 
restart treatment with dose 
reduced by 2 levels 
-If toxicity does not resolve to lower 
grade within ≥6 weeks of dose hold, 
consider permanent discontinuation 
-If Grade 3 to 4 events recur at lowest 
reduced dose, consider permanent 
discontinuation 
Pneumonitis, HUS, SJS, TEN, 
CLS, PRES of all grades 
NA 
NA 
NA 
Permanently discontinue 
ANC=absolute neutrophil, CLS=capillary leak syndrome, G-CSF=granulocyte colony-stimulating factor, HUS=hemolytic uremic syndrome, NA=not applicable, 
PRES=posterior reversible encephalopathy syndrome, SJS=Stevens-Johnson syndrome, TEN=toxic epidermal necrolysis. 


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9.3.2. 
Delay of Cycles for Other Reasons 
Once the patient has started study treatment (ie, after C1D1), study drugs may be interrupted or 
cycles may be delayed for up to 2 weeks for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention 
(eg, a holiday, anticipated study site closure, or other personal event). In addition, study drug 
may be interrupted for treatment-related AE not mentioned in Section 9.3.1 but requiring 
treatment hold for clinical reasons. However, study intervention is to be restarted within 3 weeks 
(21 days) for treatments with 21 days/cycle (nemvaleukin and/or pembrolizumab, gemcitabine, 
or 5-day dosing of topotecan) or 4 weeks (28 days) for treatments with 28 days/cycle (PLD, 
paclitaxel, or weekly dosing of topotecan) of the originally scheduled dose, unless discussed 
otherwise with the Sponsor. The reason for study intervention interruption is to be documented 
in the patient’s study record. 
9.4. 
Treatment Adherence 
All study drugs will be administered at a medical facility or study site by study staff. The clinical 
research associates will confirm that the study drugs were administered and documented in the 
patient’s eCRFs during site visits. 
9.5. 
Storage, Handling, Accountability, and Disposal of Study Drugs 
The Nemvaleukin Alfa Directions for Use and/or Pharmacy Manual will be distributed to the 
study sites and will provide in-use storage conditions and duration of time within which it should 
be used. Details on preparation and administration of pembrolizumab are provided in the 
pembrolizumab Pharmacy Manual. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
after reconstitution and prior to administration. Discard the drug product vial if visible particles 
are observed. 
The study site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Following completion and verification of accountability logs, all unused and used packages must 
be destroyed. Packages may be destroyed on-site according to GCP and site practice. 
Alternatively, the Sponsor may arrange for destruction with a third-party vendor operating in 
accordance with GCP and/or Good Manufacturing Practice, as applicable. 
Investigators choice chemotherapy (PLD, paclitaxel, topotecan, gemcitabine) is locally sourced 
and should be handled and stored accordingly. 


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10. 
STUDY PROCEDURES AND ASSESSMENTS 
10.1. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall SOA is described in Table 2 
(Arms 1 and 3), Table 3 (Arm 2), and Table 4 (Arm 4). 
There may be rare circumstances beyond the patient’s or site’s control in which patients are not 
able to come to the site for protocol-specified site visits. These would include states of 
emergency, including natural disasters, public health mandates, etc. (See Appendix 5 for risk 
mitigation strategies related to the COVID-19 outbreak.) If this occurs, sites, in consultation with 
Mural and the IRB/EC, should evaluate whether alternative methods for safety assessments 
(eg, phone contact, virtual visit/telemedicine, alternative location for assessment, including local 
labs or imaging centers) can be implemented when necessary and feasible. Sites, in consultation 
with the Sponsor and the IRB/EC, should also evaluate whether these alternative methods would 
be sufficient to assure the safety of patients. The implementation of alternative processes should 
be consistent with the protocol to the greatest extent possible. Investigators should document the 
alteration of any study conduct and the reason for any contingency measures implemented in 
source documents and in the EDC system. 
See Appendix 6 for details on data quality assurance. 
10.1.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the patient by the 
Investigator or designated study personnel as outlined in Section 13.6.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential patient. If tumor tissue is to be collected for 
central IHC testing of PD-L1 status prior to Screening, a pre-screening ICF will be obtained. 
10.1.2. 
Eligibility Review 
An eligibility review will be conducted by the Investigator during Screening using the patient 
inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. The site will share the 
screening checklist with the Sponsor and await Sponsor’s review prior to enrollment of patients 
according to operational plan. The most recent laboratory results before C1D1, including 
repeated assessments during the Screening Period or on C1D1 (prior to randomization and 
predose), should be used to assess eligibility. C1 must be scheduled within the 21-day screening 
window. 
10.1.3. 
Demographics and Medical History 
Patient’s demographic data and medical history will be reviewed and documented at 
pre-specified time point(s). 
10.1.4. 
Prior and Concomitant Medication Review 
At pre-specified time point(s), prospective patients will be asked for a history of anticancer 
medications and a history of all the medications they have taken in the last 30 days, including 


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prescription and nonprescription medications, vitamins and supplements including herbal 
supplements, and recreational drug use. 
10.1.4.1. Prior and Concomitant Medication 
The name, dose, regimen, route of administration, start and stop dates, and the indication for use 
of all medications will be recorded. Medications will be categorized using the World Health 
Organization-Anatomical Therapeutic Chemical classification system. 
10.1.4.2. Anticancer Medication 
Information collected on prior anticancer medications as well as subsequent anticancer 
medications will be collected to the greatest degree of detail possible and will include the 
following information on all previous and subsequent anticancer treatments (including systemic 
therapy, local therapy, topical therapy, and/or hormonal therapy): 
• Medicinal agents used (approved and/or investigational) 
• Start and stop dates 
• Best response by line of therapy 
• Reason for discontinuation (ie, AE, progression, etc) 
10.1.5. 
Randomization 
The pembrolizumab monotherapy arm (Arm 2) met its pre-specified futility criteria at the 
planned futility analysis and was closed to enrollment as of 31 Aug 2023, per the 
recommendation of the IDMC. The nemvaleukin monotherapy arm (Arm 3) did not meet its 
pre-specified futility criteria at the planned futility analysis and the IDMC recommended 
continuation. Under protocol version 4.0, the nemvaleukin monotherapy arm (Arm 3) reached its 
intended enrollment and thus closed. Because no changes have been made to the objectives 
related to Arm 3 in protocol version 5.0, the Arm 3 number of patients was not recalculated. 
Therefore, in protocol version 5.0, eligible patients will continue to be enrolled in the remaining 
2 arms and will be centrally allocated with a randomization ratio of 1:1 to the Combination and 
Chemotherapy arms (Arm 1 and Arm 4, respectively): 
• Arm 1: nemvaleukin and pembrolizumab combination therapy 
• Arm 2: pembrolizumab monotherapy (closed) 
• Arm 3: nemvaleukin monotherapy (closed) 
• Arm 4: Investigator’s choice chemotherapy. Options for protocol-specific 
Investigator’s choice include one of the following: PLD, paclitaxel, topotecan, or 
gemcitabine. The Investigator will pre-select the Investigator’s choice treatment 
before the randomization of each patient. 
To ensure equal distribution of prognostic factors and selection of chemotherapy in the study 
arms, patients will be stratified according to the following parameters: 
• PD-L1 status (CPS ≥10 vs CPS <10) 
• Histological subtype (high-grade serous vs non-high-grade serous) 


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• Investigator’s choice chemotherapy (paclitaxel vs other chemotherapies) 
Patients should begin C1D1 within 7 days following randomization. 
10.2. 
Efficacy Assessments 
10.2.1. 
Tumor Assessment 
Tumor assessment is to be performed using tumor imaging. In addition, histology, cytology, 
and/or ultrasound may be used for disease assessment. 
• CT scans and/or MRI are mandatory for the extent of disease assessment. 
− Conventional or, preferably, spiral CT scans with (and possibly without) IV 
contrast and possibly oral and/or rectal contrast (at the discretion of the attending 
radiologist) should be performed with contiguous cuts of ≤5 mm thickness and 
appropriate reconstructions in multiple dimensions. 
− MRI with and/or without gadolinium (at the discretion of the attending 
radiologist) should be performed with contiguous cuts of ≤5 mm thickness and 
appropriate reconstructions in multiple dimensions. 
− For both of the above modalities, anatomic/organ specific protocols should be 
followed, as appropriate, at the discretion of the attending radiologist and 
consistent with individual institutional standards. For each patient, consistency in 
the choice of imaging modality(ies) and protocol(s) should be maintained to the 
greatest extent possible throughout the study, except when this is deemed by the 
attending radiologist and/or Investigator to be unsafe, inadequate, or not in the 
best interest of the patient (eg, on study development of a CT contrast allergy). 
• Positron emission tomography scan alone will not be considered adequate for 
assessment of disease. Complementary CT scans and, when applicable, cytologic or 
histologic evaluation should be performed, as appropriate. 
• Histology and/or cytology could be considered during the study to confirm if new 
lesions is malignant (eg, new pleural effusion, etc), except for CNS metastases. 
• Although CT scan/MRI is the preferred method to assess all lesions throughout the 
study, the dimensions of superficial lesions (typically cutaneous or SC) may be 
documented by photographs with measuring tape and/or calipers in place in order to 
collect lesion measurements, whenever feasible. If superficial lesions are identified as 
target or nontarget lesion, the photograph must be taken in duplicate, and 1 copy must 
be sent for blinded independent central review. The superficial lesion must be 
followed throughout the study using the same method. 
• Deep SC lesions and other amenable lesions (eg, lymph nodes) may be measured and 
documented by ultrasound (in addition to the requisite CT and/or MRI examinations), 
and ultrasound guided tissue sampling should be attempted per institutional standards 
when deemed safe and feasible by the attending radiologist. 
It is requested that the method used for baseline disease assessment is maintained throughout the 
study. Tumor assessment should include all appropriate procedures to document the full extent of 


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the patient’s neoplastic disease (eg, relevant imaging of chest, abdomen, and/or pelvis) according 
to RECIST v1.1. Scans used for screening disease assessment that were performed previously as 
part of routine clinical management are acceptable to use if they are of diagnostic quality, have 
anatomic extent to cover the entirety of disease involvement, were performed within 28 days 
prior to C1D1, and the method used for the scan can be maintained throughout the study. 
Assessments will be based on Investigator review (including centralized review for sensitivity 
analysis) of the radiographic or photographic images as defined by RECIST v1.1; tumors are 
assessed as CR, PR, SD, or PD (Eisenhauer et al, 2009). Tumor images will be collected, stored, 
and reviewed centrally for blinded independent central review in addition to the Investigator 
review. A manual will be provided to sites with instructions on how to collect and transmit tumor 
images to the central imaging vendor. 
Patients with history of brain metastases or a suspicion of brain metastases must have a brain 
MRI at baseline. In these patients, brain MRI does not need to be performed at baseline if 
appropriate CNS imaging confirming absence of metastatic disease has been performed within 
28 days prior to the first dose of study drug and is available for review by the respective 
investigational site. 
For patients being administered investigational study drugs (ie, Arms 1, 2, 3), it is recommended 
that disease progression be confirmed 4-6 weeks later prior to discontinuation of treatment. For 
all patients, a confirmatory scan is required for the first demonstration of a PR or better and 
should be performed at no sooner than 4 weeks and no later than 6 weeks after the demonstration 
of a PR or better. 
10.2.2. 
Survival Status 
Patients will be followed for survival every 3 months (±15 days) or more frequently to assess for 
survival status starting from the EOT Visit, for up to 3 years from first dose of study drug. These 
assessments can be done in person or by phone. If a patient withdraws consent from the study 
treatment and does not consent to continued follow-up or is lost to follow-up, the Investigator or 
site study team may consult public records (eg, obituary, etc) to collect patient’s survival status. 
10.3. 
Safety Assessments 
10.3.1. 
Adverse Event Monitoring 
AE data collection will begin after a patient signs the ICF. During pre-screening period, AEs 
resulting from the protocol-specified procedure must be reported if the event is considered 
related to study procedure. 
For all arms, all AEs (including SAEs) from the time of randomization until completion of the 
30-day Safety Follow-up Visit must be reported by the Investigator; AE (including SAE) 
collection will stop if new anticancer therapy is initiated. However, SAEs will be collected for 
patients in Arms 1 and 2 through 90 days after the EOT or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier. For all arms, 
any SAE brought to the attention of an Investigator at any time outside the time specified above 
must be reported immediately to the Sponsor if the event is considered related to study 
intervention. 


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All AEs (including SAEs) will be followed by the Investigator until resolution, return to the 
baseline level, deemed stable by the Investigator, until the patient is deemed by the Investigator 
to be formally lost to follow up, or until death of the patient. 
The Investigator, Medical Monitor, and Sponsor will review the collected data regularly for 
identification/verification of AEs. All patients will be assessed routinely for AEs as outlined in 
the SOA. All AEs observed will be graded using NCI CTCAE version 5.0 (sites will receive 
notification when a higher version of NCI CTCAE becomes available and has been approved by 
the Sponsor for implementation). Refer to the NCI CTCAE website for descriptions of Grades 1 
through 5 for AEs. 
Patients will be instructed by the Investigator or designee to report the occurrence of any AE. All 
volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
AEs and SAEs are defined in Section 10.3.1.1 and Section 10.3.1.3, respectively. 
Section 10.3.1.5 provides guidance on the monitoring and recording requirements for AEs. 
Section 10.3.1.6 provides guidance on the reporting requirements for SAEs and pregnancy. For 
dose interruptions and discontinuation rules based on AEs, see Section 9.3.1. 
10.3.1.1. Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient who has 
been administered a pharmaceutical product. The occurrence, which may or may not have a 
causal relationship with the investigational treatment, may include any clinical or laboratory 
change that does not commonly occur in that patient and is considered clinically significant. 
Illnesses presenting prior to the patient signing the ICF are considered to be pre-existing 
conditions and are documented on the medical history eCRF. Pre-existing conditions that worsen 
during the study will be considered AEs and will be entered on the AE eCRF. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the Investigator. An abnormal laboratory value, in and of itself, may not be an AE. 
An abnormal laboratory value may be considered an AE under any of the following conditions: 
• It is clinically significant 
• It is an SAE (eg, it requires hospitalization) 
• It requires medical intervention (eg, blood transfusion) 
• It requires a change or delay in the administration of study drug(s) or permanent 
discontinuation of study drug(s) 
Clinically significant laboratory values will be considered AEs and recorded as such on the 
eCRFs. Laboratory values that do not meet one of the above criteria are not required to be 
reported as AEs. 
Pregnancy is not considered an AE, although a patient will be discontinued from treatment if a 
pregnancy occurs. As described in Section 10.3.1.6, the pregnancy must be reported to the 
Sponsor, and additional follow-up may be required. 


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10.3.1.2. Definition of Nemvaleukin Adverse Events of Special Interest (AESIs) 
AESIs are known or potential risks following nemvaleukin administration for which additional 
guidance is provided. These include IRR/CRS, CLS, and irAEs that may occur following 
administration of nemvaleukin. Investigators should use their medical judgment to determine if 
AEs meet the definition of an AESI as described below. All AESIs should be entered in the 
appropriate eCRF. All ≥Grade 3 AESIs should be entered in the appropriate eCRF within 
1 business day of discovery. (Note: Any AESI that meets the definition of an SAE as described 
in Section 10.3.1.3 must be reported as described in Section 10.3.1.6). All medications used to 
manage these AESIs should be captured in appropriate eCRF forms. All complications resulting 
from an AESI, such as acute kidney injury or cardiac dysfunction, should be captured separately 
in the appropriate eCRF forms. Additional information may need to be collected in the 
supplemental AESI eCRF. 
IRR/CRS: IRR/CRS can occur following nemvaleukin administration. The disorders are 
characterized by the occurrence of at least 2 of the following events: fever, tachypnea, headache, 
chills, shakes, itching, tachycardia, hypotension, rash, and/or hypoxia (Shimabukuro-Vornhagen 
et al, 2018). For more details refer to the IB. More severe forms of IRR/CRS may be associated 
with myalgia, change in mental status, pulmonary infiltrates, metabolic acidosis, hypotension 
requiring vasopressors, hypoxia requiring supplemental oxygen (FiO2 ≥40%) and/or acute 
kidney injury. When IRR/CRS is suspected, collection of trypase laboratory tests is 
recommended to aid diagnosis. As sepsis/septic shock can also present with fever, chills, and/or 
hypotension, it is important to rule out any infections. 
IRR/CRS reactions are different from allergic/hypersensitivity reactions, which are believed to 
be due to IgE-mediated mechanisms. Development of anti-drug antibodies, especially IgE 
antibodies, can cause allergic reactions. However, typically the onset of anti-drug antibodies 
occurs after 7 to 11 days and following repeated dosing. While many symptoms of 
allergic/hypersensitivity reaction are like IRR/CRSs, allergic/hypersensitivity reactions generally 
present with bronchospasm, urticaria, wheezing, angioedema, and anaphylactic symptoms. 
For management of IRR/CRS refer to Section 9.3.1. 
CLS: CLS is a disorder characterized by loss of vascular tone and release of plasma proteins and 
fluid into the extracellular space (Siddall et al, 2017). This syndrome is observed in patients who 
demonstrate a state of generalized leaky capillaries following shock syndromes, low-flow states, 
ischemia-reperfusion injuries, toxemias, medications, or poisoning. Typical clinical presentation 
includes a triad of hypotension, edema, and hypoalbuminemia. Hemoconcentration (high 
hematocrit) and reduced urine output is commonly observed. Severe forms of CLS may be 
associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial 
infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, 
renal insufficiency, generalized edema, mental status changes, multi-organ failure, and death. 
For management of CLS, refer to Section 9.3.1. 
irAEs: An irAE is a side effect associated with the increased activity of the immune system that 
affects one or more organs of the body such as the skin (eg, Stevens-Johnson syndrome and toxic 
epidermal necrolysis), gastrointestinal tract (colitis), endocrine system (endocrinopathies such as 
hypothyroidism), liver (hepatitis), kidney (nephritis), musculoskeletal system (arthritis), and 
lungs (pneumonitis). Early recognition and initiation of treatment is critical to reduce 


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complications. Diagnostic work-up is dependent on the organ system involvement and may 
include biopsy to verify the clinical diagnosis, per Investigator discretion. 
irAEs occurring in any treatment arm must be reported with appropriate relationship to study 
drug. 
For management of irAEs, refer to Section 9.3.1. 
10.3.1.3. Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality, which meets one or more 
of the following criteria: 
• Results in death 
• Is life-threatening. The patient is at immediate risk of death from the reaction as it 
occurs. This does not include a reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
jeopardize the patient and/or require intervention to prevent one of the other outcomes listed 
above. 
Progression of underlying malignancy is not considered an AE or an SAE. Death that is 
secondary to disease progression will not be reported as an SAE. However, disease progression 
and outcome, as assessed by the Investigator, will be recorded on the eCRF. 
Hospitalization for up to 24 hours to facilitate protocol-mandated procedures or IV 
administration of fluids or drugs does not require an SAE report. Planned hospital admission for 
protocol-related biopsy collection or hospitalization in an inpatient unit for a nonmedical reason 
(ie, social stay admission) during the study in the absence of untoward medical occurrence will 
not be considered an SAE. Overnight stay for observation, stay at emergency room for less than 
24 hours, or treatment on an out-patient basis do not constitute a hospitalization. However, 
medical judgement must always be exercised, and when in doubt, the case should be considered 
serious (ie, if case fulfills the criteria for a medically important event). 
10.3.1.4. Relationship to Study Drug or Procedure 
The assessment of individual study drug relationships to each AE will be reported on the 
appropriate source document (and SAE form, in the event of an SAE) by the Investigator (or 
designated Sub-Investigator) according to his or her best clinical judgment. The criteria listed in 
Table 20 should be used to guide this assessment. Please note that not all criteria must be present 
to be indicative of the drug relationship. All study drugs are considered “test drugs” for the 
purposes of the definitions listed in the table. 


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For patients receiving both nemvaleukin and pembrolizumab (Arm 1), assessment of relationship 
should be assigned for each drug where possible. 
Table 20: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for Assessment 
Related 
There is evidence of exposure to study drug(s). The temporal sequence of the 
AE onset relative to the administration of the study drug(s) is reasonable. The 
AE is more likely explained by the study drug(s) than by another cause. 
Not related 
Patient did not receive the study drug(s) OR temporal sequence of the AE 
onset relative to administration of the study drug(s) is not reasonable OR 
there is another obvious cause of the AE. 
AE=adverse event. 
10.3.1.5. Monitoring and Recording of Adverse Events 
All patients will be assessed routinely for AEs as outlined in the SOA. All AEs observed will be 
graded using NCI CTCAE version 5.0 (sites will receive notification when a higher version of 
NCI CTCAE becomes available and has been approved by the Sponsor for implementation). 
Refer to the NCI CTCAE website for descriptions of Grades 1 through 5 for AEs. For AEs that 
are not specified in the NCI CTCAE, the following criteria should be used to guide the 
assessment of intensity (severity grade): 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL (Note: Instrumental ADL refer to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (Note: Self-care ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.) 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Patients will be instructed by the Investigator or designee to report the occurrence of any AE. All 
volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The Investigator will evaluate all AEs regarding any causal relationship to the study drug(s) (see 
Section 10.3.1.4), the intensity (severity grade) of the event, action taken, and patient outcome. 
For clinical study safety reporting purposes, the reference safety information approved for 
nemvaleukin and pembrolizumab will be based on the IB version at the time of the event 
occurrence. The reference safety information for all other chemotherapy drugs will be their 
relevant prescribing information. 


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10.3.1.6. Reporting of Serious Adverse Events and Pregnancy 
All SAEs and pregnancies must be reported within 24 hours of discovery, by emailing or faxing 
the report to the following: 
Attention: PPD Safety 
Toll Free Fax: +1 (888) 488-9697 
Direct Dial Fax: +1 (919) 654-3849 
Email: WILSafety@ppd.com 
A written report for all SAEs should be submitted on the SAE form provided for this purpose. 
The SAE report must include the Investigator’s opinion as to whether the event is related to 
study drug. If there is a reasonable possibility the event is related to study drug(s), evidence to 
support this assessment must also be provided. 
10.3.2. 
Physical Examination 
Physical examinations will be performed at pre-specified time points. A focused physical 
examination shall address anatomic sites and organ systems at which signs and symptoms are 
present and/or that are known or suspected to be involved with the patient’s underlying 
malignancy, following institutional standards of care. 
Physical examinations will be performed at pre-specified time points. A full physical exam at 
baseline will be needed to assess whether all body systems are normal, abnormal but clinically 
not significant, or abnormal and clinically significant. This full physical examination will serve 
as a baseline physical exam. 
A focused/directed physical examination shall address anatomic sites and organ systems at which 
signs and symptoms are present and/or that are known or suspected to be involved with the 
patient’s underlying malignancy, following institutional standards of care. Focused physical 
exams will collect information on whether the relevant body system(s) are abnormal but 
clinically not significant, or abnormal and clinically significant findings. New clinically 
significant findings from focused examination should be recorded as AEs. 
10.3.3. 
Vital Signs, Electrocardiograms, and Left Ventricular Ejection Fraction 
Vital signs (eg, blood pressure, pulse, respiratory rate, and body temperature), height, and weight 
will be assessed at pre-specified time point(s). Blood pressure, pulse, and respiratory rate will be 
measured after the patient has been resting in a seated or supine position for at least 5 minutes. 
A 12-lead ECG will be conducted at pre-specified time point(s). ECGs should be performed in 
singlet. 
Baseline LVEF is collected if PLD is selected as Investigator’s choice chemotherapy. 
On-treatment LVEF assessments only apply to patients receiving PLD. The same assessment 
technique (multiple gated acquisition or echocardiogram) should be conducted throughout 
treatment. If patient LVEF drops below normal or by at least 15% from baseline, treatment with 
PLD should be discontinued. 


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10.3.4. 
Laboratory Assessments 
10.3.4.1. Hematology, Biochemistry, Urinalysis, and Coagulation 
Blood and urine samples for clinical laboratory assessments will be collected at pre-specified 
time points. Specific hematology, biochemistry, urinalysis, and coagulation assessments are 
listed in Appendix 3. A Laboratory Manual is to be provided to the site by the central laboratory 
with details regarding the collection, handling, and shipping of samples for clinical laboratory 
assessments. Fasting is not required prior to sample collection for clinical laboratory 
assessments. 
Study sites may also utilize their local laboratory for dosing decisions and to ensure 
safety-related results are available for review prior to dosing. 
10.3.4.2. Pregnancy Testing 
A serum or urine pregnancy test, performed by local laboratory, will be administered to all 
WOCBP at pre-specified time points. At the Screening Visit, results must be negative for the 
patient to be eligible for the study. WOCBP must have a negative pregnancy test (serum or 
urine) within 3 days (72 hours) before the first dose of study drug is administered in every cycle. 
If pregnancy testing is performed within 3 days (72 hours) of dosing, sampling does not need to 
be repeated on the day of dosing. 
• For sites in France and Norway only: after treatment discontinuation, pregnancy 
testing in heterosexually active WOCBP must continue to be assessed monthly for 
30 days in Arm 3, for 120 days in Arm 1 and Arm 2, and for the recommended 
duration of the contraception in the approved label and/or institutional guidelines for 
the specific Investigator’s choice chemotherapy in Arm 4. 
Section 10.3.1.6 provides guidance on the reporting requirements for pregnancies. 
10.3.5. 
Eastern Cooperative Oncology Group Status 
The ECOG status is used to evaluate the patients’ activity status and will be evaluated at 
pre-specified time points. Possible scores are from 0 to 5. Descriptions of activity status are 
presented in Appendix 4. 
10.4. 
Assessment of Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity 
Samples for PK, pharmacodynamics, and immunogenicity testing will be obtained at 
pre-specified time points. 
The PK, pharmacodynamic, and immunogenicity sample analyses will be conducted by a central 
laboratory identified by the Sponsor. A Laboratory Manual is to be provided to the site by the 
central laboratory with details regarding the collection, handling, and shipping of samples for 
PK, pharmacodynamic, and immunogenicity testing. Samples will be collected in accordance 
with the site’s usual procedures. 


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10.4.1. 
Pharmacokinetics 
Serum samples for evaluation of nemvaleukin PK and/or pembrolizumab PK will be obtained 
from each patient at pre-specified time points. A validated electrochemiluminescence method 
will be used for the quantitation of nemvaleukin in human serum. Serum samples for evaluation 
of pembrolizumab PK will be stored for potential analysis. 
10.4.2. 
Pharmacodynamics and Biomarkers 
The pharmacodynamic response of various biomarkers will be assessed in blood and serum 
samples collected from all patients in the study. Plasma samples will also be collected for 
isolation of circulating tumor DNA from patients at pre-specified time points. Additional 
biomarker analyses may be performed on tumor tissue samples. 
10.4.2.1. Blood-Based Biomarkers 
The pharmacodynamic effect of nemvaleukin will be assessed by measuring circulating 
CD8+ T cells, Tregs, and NK cells in peripheral blood from each patient at pre-specified time 
points. Expression of IL-2Rs on immune cells and T cell receptor clonality may also be assessed. 
In addition, serum samples will be obtained from each patient at pre-specified time points. 
Concentration of multiple pro-inflammatory cytokines including interferon-γ, tumor necrosis 
factor-α, IL-1β, IL-6, and IL-10, and other soluble proteins will be determined using validated 
assay kits. 
Circulating tumor DNA may be isolated from plasma collected at pre-specified time points and 
may be subject to genetic and epigenetic analyses. 
10.4.2.2. Tumor Tissue Assessment 
Guidance on collection of tumor biopsies and archival tumor tissue is provided below. Tumor 
biopsies and archival tumor tissues may be used for analyzing tumor cells and tumor-infiltrating 
immune cells by methods such as IHC and/or immunofluorescence. They may also be used for 
gene expression analysis using methods such as RNA sequencing or NanoString. In addition, 
they may be used for obtaining mutation status of tumors including mutation burden of tumors 
by DNA sequencing analysis. Note: if surgery is planned during the study, collection of tissue 
and blood samples is recommended with appropriately documented consent under the optional 
biopsy collection procedures. 
Archived Tumor 
Patient must provide tumor tissue collected from prior cytoreductive surgery or any archival 
tumor tissue collected after diagnosis of EOC or fresh biopsy (newly obtained tissue at 
Screening). Fresh biopsy is preferred and highly recommended. Collection of tumor tissue 
samples from both prior cytoreductive/debulking surgery and fresh biopsy are recommended 
(when possible) to understand changes in the tumor microenvironment during treatment. The 
tumor tissue sample should be made available for central testing of PD-L1 status prior to 
randomization. In cases when archival tissue has been taken from a target lesion(s), baseline 
imaging used to document initial extent of disease must have been performed after sampling of 
archival tissue. Archival tissue may provide useful information about the pretreatment state of 
immune activation in the respective patient’s tumor(s). 


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If the tumor tissue is to be collected for central testing of PD-L1 status prior to Screening, a 
pre-screening ICF will be obtained. A patient can be pre-screened while on current therapy if the 
patient is interested in participating in the study in case of disease progression (the full ICF still 
needs to be obtained and the patient needs to meet the remaining eligibility criteria at the time of 
Screening for participation in the study). The pre-screening window of Day −90 to −22 allows 
additional time for collection and processing the tissue for PD-L1 status, which may require 
more than the 21 days of the Screening Period. The pre-screening ICF does not need to be used if 
the site does not anticipate a requirement for additional time for tumor tissue collection and 
processing. 
Central PD-L1 results are required for randomization. Under extreme circumstances the medical 
monitor may pre-approve the use of local PD-L1 result for randomization if:  
• Tissue was submitted for central assessment, and the laboratory was given at least 
10 business days to run the assay, but the results did not become available in the 
expected timeframe for randomization; and 
• The local assessment was performed using DAKO 22C3 assay and the result allows 
PD-L1 status categorization (CPS ≥10 vs CPS <10). 
See Lab Manual for details on collecting archival tumor tissue. 
Tumor Biopsies 
If archival tissue is not available at baseline, patients must undergo a biopsy during Screening. 
The tumor tissue specimen provided at Screening will be archived and will serve as the baseline 
sample. 
In patients with accessible lesions, an additional tumor biopsy is to be taken on-treatment as 
indicated in the SOA. This additional tumor biopsy is optional for patients but strongly 
encouraged. If patient undergoes biopsy or tissue collection any other time on study (ie, at 
progression), it is encouraged that this be utilized as the optional tumor biopsy. Only patients 
providing this optional informed consent will have the optional tumor biopsy performed. 
Neither baseline nor on-treatment biopsies shall be performed on target lesions. The on-treatment 
biopsy should be taken at the same anatomic site as the baseline biopsy, if feasible. 
Refer to the Laboratory Manual for tumor sample handling and processing information. 
10.4.3. 
Immunogenicity 
Serum samples for detection of anti-nemvaleukin antibodies and anti-pembrolizumab antibodies 
will be obtained from each patient at pre-specified time points. A validated 
electrochemiluminescence method will be used for the detection of anti-nemvaleukin antibodies. 
Additional immunogenicity characterization (eg, detection of neutralizing anti-nemvaleukin 
antibodies) may be performed as deemed appropriate. Serum samples for detection of 
anti-pembrolizumab antibodies will be stored for potential future analysis. 


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11. 
STATISTICS 
11.1. 
Sample Size Considerations 
The Chemotherapy Arm is considered the comparator arm in this study; the antitumor activity of 
nemvaleukin in combination with pembrolizumab as compared to that of Investigator’s choice 
chemotherapy in patients with PROC will be evaluated.  
The primary endpoint was changed from PFS to OS in protocol version 5.0; therefore, the 
sample size was recalculated based on OS assumptions. 
Approximately 366 patients are planned to be randomized in a 1:1 ratio into the Combination 
and the Chemotherapy arms (Arm 1 and Arm 4, respectively). It is expected that approximately 
286 deaths will have been observed between the Combination and the Chemotherapy arms at the 
final OS analysis. The study has an approximate 85% power to detect an OS HR of 0.7 (the 
Combination arm versus the Chemotherapy arm at an alpha level of 2.5% (1-sided). 
The sample size calculation is based on the following assumptions: 
1. 2.5% alpha is allocated to the OS endpoint 
2. OS follows an exponential distribution with a median of 10 months and 14.3 months in 
the Chemotherapy arm and Combination arm, respectively 
3. the HR is 0.7, corresponding to a 4.3 month increase in the median OS 
4. an enrollment period of 25 months; and 
5. a yearly dropout rate of 5% 
Under protocol version 5.0, approximately 450 patients are planned, including approximately 
366 patients planned across Arm 1 and Arm 4 (approximately 183 patients in each arm). Under 
protocol version 5.0, no additional patients will be enrolled in the pembrolizumab monotherapy 
or nemvaleukin monotherapy arms (Arm 2 and Arm 3, respectively). 
In order to reach 286 death events, patients may be followed longer. 
One planned efficacy interim analysis of OS will be performed when approximately 215 death 
events (approximately 75% information fraction) are observed in the 2 arms (the Combination 
and the Chemotherapy arms). The Lan-DeMets O’Brien-Fleming alpha-spending function is 
constructed to implement group sequential boundaries to control the type I error rate. 
The sample size and power calculations were performed in the software R (package “gsDesign”). 
The monotherapy arms (either pembrolizumab alone or nemvaleukin alone) are included for 
reference only to examine component effect, and no statistical comparison or testing will be 
conducted against or between these arms. 
11.2. 
Analysis Populations 
• ITT Population: The ITT Population will include all randomized patients regardless 
of the study drug received. 


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• Safety Population: The Safety Population will include all randomized patients who 
received any exposure to nemvaleukin, pembrolizumab, or Investigator’s choice 
chemotherapy. 
• Pharmacodynamic Population: The Pharmacodynamic Population will consist of all 
patients who received at least 1 dose of nemvaleukin, pembrolizumab, or 
Investigator’s choice chemotherapy and have at least 1 available post-baseline 
pharmacodynamic measurement. 
• Pharmacokinetic Population: The PK Population will consist of all patients who 
received at least 1 dose of nemvaleukin or pembrolizumab and have at least 
1 measurable serum concentration of nemvaleukin or pembrolizumab at any 
scheduled PK time point. 
11.3. 
Statistical Methodology 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables and number and percentage of patients in each category for 
categorical variables) will be provided for evaluated variables by treatment arms. Study drug is 
defined as nemvaleukin and/or pembrolizumab, or Investigator’s choice chemotherapy. 
All individual patient-level data will be presented as data listings. Missing data will not be 
imputed. 
Baseline is defined as the last non-missing value prior to each respective patient’s first dose of 
study drug. 
Multiplicity adjustment will not be applied to sensitivity analyses. Details can be found in the 
SAP. The Chemotherapy Arm consists of multiple agents depending on the Investigator’s 
choice; all these agents together will be considered as one Chemotherapy Arm. The statistical 
comparison or testing will only be conducted between the Combination Arm and the 
Chemotherapy Arm. No statistical comparison or testing will be conducted against or between 
the monotherapy arms.  
11.3.1. 
Demographics and Baseline Characteristics 
Patient disease and baseline characteristics will be summarized by treatment arms using 
frequency distribution or descriptive statistics, as appropriate. 
Demographics and baseline characteristics such as age, race, weight, ECOG status, prior line(s) 
of therapy, vital signs, and clinical laboratory data will be summarized with descriptive statistics. 
Medical history information will be coded and summarized by treatment arms for the ITT 
Population using the most recent version of Medical Dictionary for Regulatory Activities. 
Cancer disease history data will be summarized. 
11.3.2. 
Patient Disposition 
The number of patients in the ITT Population and the reasons for discontinuation from either 
treatment or from study will be summarized separately. 


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11.3.3. 
Drug Administration and Compliance 
The treatment exposure of study drug (eg, treatment duration, number of treatment cycles, 
number of infusions for each cycle, and cumulative dose received) and duration of study 
follow-up time will be summarized. 
Duration of exposure to study drug is defined for each patient as duration from C1D1 to the end 
of last cycle. 
The major protocol deviations will be summarized, and all the protocol deviations will be 
provided in the listing. 
11.3.4. 
Handling of Missing Data 
The missing data including antitumor and safety endpoints will not be imputed. 
11.3.5. 
Multiplicity Adjustments 
The overall type I error for this study is controlled at 2.5% (1-sided), fully allocated to OS. The 
statistical comparison is only performed between the Combination and Chemotherapy arms 
(Arm 1 and Arm 4, respectively).  
The Lan-DeMets O’Brien-Fleming alpha-spending function is constructed to implement group 
sequential boundaries for OS hypothesis testing to control the type I error. 
Efficacy boundaries are based on the assigned type I error rate and the projected number of 
events at study milestones. The actual boundaries will be determined from the actual number of 
events at the time of the specified interim analysis using the alpha-spending function. 
There will be no type I error rate adjustment for the interim futility analysis performed for each 
of the monotherapy arms since the monotherapy arms are not included for any statistical 
comparisons. 
11.3.6. 
Concomitant Medications 
Prior and concomitant medications will be summarized for the ITT Population using the World 
Health Organization-Anatomical Therapeutic Chemical classification system. 
11.3.7. 
Efficacy Analyses 
Antitumor activity analyses will be based on the ITT Population unless otherwise specified. 
Antitumor activity and efficacy data (including ORR, DCR, DOR, PFS, TTR, and OS) will be 
summarized. 
The monotherapy arms (either nemvaleukin alone or pembrolizumab alone) are included in the 
study for reference only and descriptive estimates of efficacy will be provided for those arms. 
Details of the analyses will be specified in the SAP. 
11.3.7.1. Primary Efficacy Analyses 
The primary efficacy endpoint is OS. The primary endpoint was changed from PFS to OS in 
protocol version 5.0 because it is considered the most appropriate primary endpoint to 
objectively demonstrate clinical benefit in the target population (El Bairi et al, 2023). 


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OS is defined as the time from randomization to death due to any cause. For patients without 
documentation of death, patients will be censored at the last known contact date or the date of 
study cut-off, whichever comes earlier. 
OS will be calculated as duration from date of randomization to the date of death or censoring. 
Survival information may be collected from publicly available sources (eg, public health 
registries or databases) for patients that have died after discontinuation from the study. 
The statistical hypothesis test, where HR is: 
H0 (Null Hypothesis): HR (combination/chemotherapy) = 1 
Ha (Alternative Hypothesis): HR (combination/chemotherapy) <1 
The treatment difference in survival will be assessed by the stratified log-rank test, and p-value 
will be reported. A stratified Cox proportional hazard model will be used for modeling the 
treatment effect between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, 
respectively). The Efron method will be used for handling the ties. The HR and its associated 
95% CI will be reported. 
OS will be displayed by Kaplan-Meier curves. Median OS and its 95% CI will be provided. The 
1-year and 2-year OS rate will be estimated using the Kaplan-Meier method. 
The censoring rule for OS is summarized in Table 21. 
Table 21: 
Censoring Rule for Overall Survival Analysis 
Situation 
Date of Death or Censoring 
Outcome 
Death during study 
Date of death 
Death 
Patient alive at data cut-off/ 
death occurred after data cut-off 
Date of cut-off 
Censored 
Patient lost to follow-up before data cut-off 
Date last known to be alive 
Censored 
Sensitivity analyses of OS: 
• OS will be compared between the Combination and the Chemotherapy arms (Arm 1 
and Arm 4, respectively) using the unstratified log-rank test based on the ITT 
Population, and p-value will be reported. The unstratified Cox proportional hazard 
model will be used to assess the treatment effect between the Combination and the 
Chemotherapy arms (Arm 1 and Arm 4, respectively) based on the ITT Population. 
The Efron method will be used for the handling of ties. The HR will be reported with 
95% CI. 
• To account for the potential non-proportional hazards effect associated with 
immunotherapies, OS will be compared between the Combination and the 
Chemotherapy arms (Arm 1 and Arm 4, respectively) using the Fleming and 
Harrington weighted log-rank test with parameter (rho=0, gamma=1) stratified by 
factors used for randomization based on the ITT Population. The p-value will be 
reported. 


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• To address the possible violation of the proportional hazard assumption, a restricted 
mean survival time with the ITT Population based on the AUC for survival will be 
implemented using different truncation points (eg, 12 months and 18 months). The 
estimated restricted mean survival time difference in OS between the Combination 
and the Chemotherapy arms (Arm 1 and Arm 4, respectively) will be reported with 
95% CIs. The SAS procedure such as RMSTREG will be used with a linear link 
function, and the model will adjust for the stratification factors. 
• Additional analyses of OS adjusting for the effect of subsequent treatment may be 
performed based on recognized methods [eg, the Rank Preserving Structural Failure 
Time model (Robins and Tsiatis 1991)], if a sufficient proportion of participants 
switch. The choice of the method will be based on an examination of the 
appropriateness of the data to the assumptions required by the method.  
11.3.7.2. Secondary Efficacy Analyses 
Progression-Free Survival 
PFS is defined as the time from randomization to the first documentation of objective tumor 
progression (by RECIST v1.1) or death due to any cause. 
For patients who have PD while on study treatment, the date of disease progression will be the 
date of the first assessment at which PD is objectively documented per RECIST v1.1 by the 
Investigator. If the patient discontinues study treatment for reasons other than documented PD 
per RECIST v1.1, then the date of disease progression will be the date of the first assessment at 
which PD is objectively documented per RECIST v1.1 by the Investigator during the Follow-Up 
Period and prior to start of new anticancer treatment. Death is considered as a confirmed PD 
event. In case PD or death are observed immediately after 2 or more missed consecutive tumor 
assessments, PFS will be censored at the date of the last tumor assessment immediately before 2 
or more missed consecutive tumor assessments. All remaining patients will be censored at the 
last known date at which the patient was considered progression-free. 
PFS will be calculated from the date of randomization to the date of PD or death, whichever 
occurs first. 
A stratified Cox proportional hazard model will be used for modeling the treatment effect 
between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, respectively). The 
Efron method will be used for handling the ties. The HR and its associated 95% CI will be 
reported. 
The median PFS will be provided along with the 95% CI. In addition, Kaplan-Meier curves will 
be provided. The 6-month, 9-month, or 1-year PFS rate will be estimated using the Kaplan-Meier 
method. 
The censoring rules for PFS are summarized in Table 22. 


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Table 22: 
Censoring Rule for Progression-Free Survival 
Cases 
Analysis 
Patients received a new anticancer 
treatment that started before PD per 
RECIST v1.1 or death 
Censored at the last assessment where the patient was 
documented as progression-free prior to the intervention 
PD per RECIST v1.1 or death at the 
next tumor assessment immediately 
after 2 or more missed consecutive 
tumor assessments 
Censored at the date of the last tumor assessment 
immediately before 2 or more missed consecutive tumor 
assessments 
PD=progressive disease, RECIST= Response Evaluation Criteria in Solid Tumors 
PFS2 (delayed PFS) analysis: PFS2 is defined as the time from randomization to subsequent 
disease progression after initiation of new anticancer therapy, or death from any cause, 
whichever occurs first. If progression after next-line therapy cannot be measured, a PFS event is 
defined as end or discontinuation of next-line treatment or death from any cause, whichever 
occurs first. Patients alive and for whom a PFS event has not been observed should be censored 
at the last time known to be alive and without second disease progression. The same statistical 
model for PFS will be used for the PFS2 analysis. 
Objective Response Rate 
ORR is defined as the proportion of patients in the analysis population who have a CR or PR. 
The best overall response is the best response recorded after initiation of study treatment until 
initial documented disease progression or start of a new anticancer treatment, whichever occurs 
first, taking into account the requirements for confirmation of CR or PR, unless otherwise 
specified. 
The analysis of ORR between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, 
respectively) will be conducted by the CMH test based on randomization stratification factors. 
The ORR difference and its associated 95% CI will be reported.  
Duration of Response: 
DOR is defined as the time from the first documentation of CR or PR to the first documentation 
of objective tumor progression or death due to any cause. Patients who never achieve CR or PR 
prior to starting any new anticancer treatment will be excluded from the analysis. DOR is based 
on a non-randomized subset of patients (specifically, patients who achieve an objective 
response). Therefore, a formal hypothesis testing will not be performed for this endpoint. 
DOR will be calculated as follows (in weeks): 
(date of disease progression/death – date of first response (CR or PR) + 1) / 7 
The distribution of DOR will be estimated using the Kaplan-Meier method. The median estimate 
of DOR will be provided along with 95% CI. Kaplan-Meier curves will also be provided. 
The censoring rule for DOR is the same as that of PFS. 


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Disease Control Rate: 
DCR is defined as the proportion of patients with objective evidence of CR, PR, or SD. For SD, 
measurements must have met the SD criteria at least once after study entry at a minimum interval 
of 6 weeks. 
The DCR will be analyzed using the CMH test based on randomization stratification factors. The 
difference and its associated 95% CI will be reported. 
Time to Response: 
TTR is defined as the time from randomization to the first documentation of CR or PR. Patients 
who never achieve CR or PR prior to starting any new anticancer treatment will be excluded 
from the analysis. No censoring observation will occur by definition. TTR is based on a 
non-randomized subset of patients (specifically, patients who achieve an objective response); 
therefore, formal hypothesis testing will not be performed for this endpoint. Comparisons 
between treatment arms will be made for descriptive purposes. 
The TTR will be calculated as follows (in weeks): 
(date of first response [Complete or Partial] – date of randomization + 1) / 7 
Cancer Antigen 125 Response 
CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline and the 
response must be confirmed and maintained for at least 28 days. The number of responders will 
be analyzed using the CMH test based on randomization stratification factors. The response 
difference and its associated 95% CI will be reported. 
In addition, the change from baseline value in CA-125 will be summarized with descriptive 
statistics. 
11.3.8. 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses 
11.3.8.1. Pharmacokinetic Analyses 
A patient listing of individual serum concentrations of nemvaleukin (and pembrolizumab as 
appropriate) will be provided. Concentration data will be summarized descriptively according to 
nominal (protocol-specified) sampling times. PK concentration data from this study may be used 
in a subsequent population PK analysis or other post-hoc analyses conducted outside of this 
study. 
11.3.8.2. Pharmacodynamic Analyses 
Blood Pharmacodynamic Analyses 
Pharmacodynamic data will be summarized descriptively, including absolute cell counts or 
proportion and concentrations at nominal (protocol-specified) time points, as well as fold change 
from baseline for circulating leukocytes (including T and NK cells) and cytokines (including 
interferon-γ, and IL6). Additional analyses may be conducted as deemed necessary upon 
exploration of data. 
A patient listing of individual pharmacodynamic data will be provided. 


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Tumor Tissue Pharmacodynamic Analyses 
Tumor biopsy samples from patients will be processed and may be analyzed by IHC and/or 
immunofluorescence for tumor-infiltrating immune cells. The baseline (pretreatment) values, 
post-treatment values, and the changes from baseline in density of immune cells in tumor tissues 
may be summarized descriptively in tables. 
Relevant markers for disease (eg, BRCA status and homologous recombination deficiency status; 
TMB scores; and PD-L1 expression) may be summarized descriptively. Additional analyses may 
be conducted as deemed necessary upon exploration of data. 
11.3.8.3. Immunogenicity Analyses 
A patient listing of individual immunogenicity data for nemvaleukin (and pembrolizumab as 
appropriate) will be provided. 
Immunogenicity endpoints include the following: 
• Presence of anti-drug antibodies 
• Titer of anti-drug antibodies 
• Frequency of the presence of anti-drug antibodies by relevant treatment arms 
Time of onset of immunogenicity and time of resolution of immunogenicity will be calculated 
and summarized. (Time of onset is defined as the first time point with a positive result for ADA; 
time of resolution is defined as the first time point when the previously observed positive for 
ADA returns to negative for ADA.) 
Additional immunogenicity characterization (eg, presence of neutralizing ADAs) may be 
summarized as deemed appropriate. 
11.3.9. 
Safety Analyses 
11.3.9.1. General Considerations 
All safety endpoints will be summarized for the Safety Population. Safety evaluations will be 
based on AEs, vital signs, weight, clinical laboratory tests, and ECGs. 
11.3.9.2. Adverse Events 
AEs will be coded using the most recent version of MedDRA. TEAEs are defined as AEs that 
that have an onset on or after the day of the first dose of study drug or increases in severity after 
the first dose of study drug. Disease progression will not be captured as an AE or SAE. Death 
due to disease progression will not be captured as an SAE. 
Analyses of AEs will include TEAEs that were collected during the safety reporting period as 
defined in Section 10.3.1.5. Events where the onset date was the same as the study drug start date 
will be assumed to be treatment-emergent, unless the study drug start time and the AE start time 
are collected, and the AE start time is prior to the study drug start time. Handling of missing or 
incomplete onset dates will be described in the SAP. 


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TEAEs will be summarized by PT and by SOC. Patients reporting more than one AE within a 
SOC will be counted only once for that SOC. Patients reporting the same AE more than once 
will be counted only once for that PT. 
The severity of TEAEs will be assessed by NCI CTCAE. For TEAEs that are not specified in the 
NCI CTCAE, severity grade is assigned by the criteria in Section 10.3.1.5. If a patient has the 
same AE on multiple occasions, the highest severity recorded for the event will be presented in 
the AEs by severity table. 
An overview table, including the number of patients with any TEAEs, SAEs, TEAEs related to 
study drug, TEAEs by severity, TEAEs leading to treatment discontinuation, TEAEs leading to 
dose reduction, TEAEs leading to dose interruption, and TEAEs leading to death will be 
summarized. 
In addition, the TEAEs will be summarized by treatment arm for the following: 
• TEAEs and related TEAEs by SOC and PT 
• TEAEs and related TEAEs by SOC, PT, and grade 
• Grade 3-4 TEAEs by SOC and PT 
• Grade 3-4 related TEAEs by SOC and PT 
• SAEs and related SAEs by SOC and PT 
• TEAEs and related TEAEs by PT by decreasing order of frequency 
• TEAEs and related TEAEs leading to dose reduction by SOC and PT 
• TEAEs and related TEAEs leading to dose interruption by SOC and PT 
• TEAEs and related TEAEs leading to treatment discontinuation by SOC and PT 
• TEAEs and related TEAEs leading to death 
• AESIs and related AESI 
Listings will be provided for all AEs, SAEs, AESI, TEAEs leading to treatment discontinuation, 
TEAEs leading to dose reduction, TEAEs leading to dose interruption, and TEAEs leading to 
death. 
11.3.9.3. Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Only scheduled 
laboratory parameters will be included in the laboratory results summaries, unless specified 
otherwise. All laboratory data, including those collected at unscheduled visits, will be included in 
the listings. 
Results of clinical laboratory tests will be summarized for pre-specified visits by treatment arm 
for the actual values and for change from baseline. Data collected at the EOT Visit will be 
included as one time point. 
In addition, where applicable, hematology and chemistry laboratory determinations will be 
categorized according to NCI CTCAE grades and shifts from baseline NCI CTCAE grades to 
maximum and final post-baseline grades will be summarized. The baseline and final grades will 


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be defined respectively as the grade of the last measurement collected prior to the first dose of 
study drug, and as the last post-baseline measurement collected no more than 30 days after the 
last dose of study drug. 
The maximum NCI CTCAE toxicity grade value will be the value with the highest NCI CTCAE 
toxicity grade collected after the first dose of study drug and within 30 days following study drug 
discontinuation. In cases where multiple values are collected on the same day, the maximum 
grade value will be selected as the value for that day. 
Detailed listings of data for patients experiencing NCI CTCAE grade ≥3 hematology and 
chemistry values will be provided. All measurements collected after the first dose of study drug 
and within 30 days following study drug discontinuation will be included in these listings. 
The number of patients who meet the following criteria will be summarized and corresponding 
listing will be presented: 
An elevated AST or ALT laboratory value that is ≥3 × ULN, an elevated total bilirubin 
laboratory value that is ≥2 × ULN, and an ALK-P laboratory value that is <2 × ULN. 
11.3.9.4. Vital Signs and ECG 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values after the first dose of study 
drug will be presented for pre-specified visits. Tables will also present the shifts from baseline. 
All vital sign data will be presented in the patient data listings. In addition, a detailed data listing 
for patients experiencing potentially clinically significant events will be provided. 
Electrocardiograms 
Data for patients experiencing clinically significant ECG changes will be provided. 
11.3.9.5. ECOG Status 
The ECOG status assesses the patients’ activity status (Appendix 4). Descriptions of activity 
status are presented as possible scores from 0 to 5. The number and percentage of patients with 
baseline score versus post-baseline scores will be summarized by treatment arm in a shift table. 
11.3.10. 
Patient-Reported Outcomes: Health-Related Quality of Life 
FACT-O 
The FACT-O is a 39-item questionnaire about the past 7 days using a 5-point Likert-type scale. 
It includes 5 subscale domains (physical well-being, social/family well-being, emotional 
well-being, functional well-being, and ovarian subscale). The scoring guideline is summarized in 
the SAP. 
EQ-5D-5L 
The EQ-5D-5L is a validated quality of life questionnaire developed by the EuroQol Group in 
order to provide a simple, generic utility measure for characterizing current health states of 
patients. The EQ-5D-5L is designed for self-completion by patients. It consists of 2 parts – the 
EQ-5D-5L descriptive system and the VAS. 


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The EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels. 
The 5-dimensional, 5-level systems are converted into an index value. Values for theoretically 
possible health states are calculated using a regression model and weighted according to the 
social preferences of the US population (Van Hout et al, 2012). 
The VAS records the respondent’s self-rated health on a vertical VAS. The VAS “thermometer” 
has 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the 
bottom. This information can be used as a quantitative measure of health outcomes as judged by 
the individual respondents. The EQ-5D-5L self-reported VAS data generates information on the 
self-perceived overall HRQoL. During the Long-term Follow-up Period, only the VAS will be 
administered to patients in all treatment arms. 
The HRQoL endpoints will be analyzed based on the ITT Population who have the baseline and 
at least one post-baseline score. The absolute values and changes from baseline at each 
administration time point in total score and subscale domain scores for the FACT-O and 
EQ-5D-5L index and VAS scores will be descriptively summarized. The statistical comparison 
between the Combination and Chemotherapy arms will be conducted for selected items, domain, 
or total score as described in the SAP. 
11.4. 
Randomization/Method of Assigning Patients to Treatment 
Per the original study design, patients were centrally allocated in a randomized fashion (3:1:1:3) 
to receive either: 
• Arm 1: nemvaleukin and pembrolizumab combination therapy 
• Arm 2: pembrolizumab monotherapy (closed) 
• Arm 3: nemvaleukin monotherapy (closed) 
• Arm 4: Investigator’s choice chemotherapy. Options for protocol-specific 
Investigator’s choice include one of the following: PLD, paclitaxel, topotecan, or 
gemcitabine. The Investigator will pre-select the Investigator’s choice treatment 
before the randomization of each patient. 
The pembrolizumab monotherapy arm (Arm 2) met its pre-specified futility criteria at the 
planned futility analysis and was closed to enrollment as of 31 Aug 2023, per the 
recommendation of the IDMC. The nemvaleukin monotherapy arm (Arm 3) did not meet its 
pre-specified futility criteria at the planned futility analysis and the IDMC recommended 
continuation. Under protocol version 4.0, the nemvaleukin monotherapy arm (Arm 3) reached its 
intended enrollment and thus closed. Because no changes have been made to the objectives 
related to Arm 3 in protocol version 5.0, the Arm 3 number of patients was not recalculated. 
Therefore, in protocol version 5.0, eligible patients will continue to be enrolled in the remaining 
2 arms and will be centrally allocated with a randomization ratio of 1:1 to the Combination and 
Chemotherapy arms (Arm 1 and Arm 4, respectively). 
To ensure equal distribution of prognostic factors and chemotherapy partners in the study arms, 
patients will be stratified according to the following parameters: 
• PD-L1 status (CPS ≥10 vs CPS <10) 


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• Histological subtype (high-grade serous vs non-high-grade serous) 
• Investigator’s choice chemotherapy (paclitaxel vs other chemotherapies) 
11.5. 
Blinding and Independent Data Monitoring Committee 
An IDMC will be established by the Sponsor to analyze and interpret the data for the interim 
analysis. Members will include experts in oncology and biostatistics who are not participating in 
this study at any capacity and do not have any external conflict of interest for the study. The 
IDMC members and specific duties will be fully described in an IDMC charter. 
The Sponsor’s study team members will remain blinded for any aggregate antitumor efficacy 
data or efficacy results by assigned treatment group during the study conduct. 
11.6. 
Interim Analyses 
The interim analyses planned in this study are described below. All the analyses will be 
conducted by an independent statistician under the guidance of IDMC. The Sponsor’s study team 
members will be blinded for any aggregate antitumor efficacy data or results by assigned 
treatment group during the study conduct. More details can be found in the IDMC charter. 
Interim Futility Analysis of ORR in Each Monotherapy Arm 
The monotherapy arms (either nemvaleukin alone or pembrolizumab alone) are included in the 
study as reference arms to isolate the component effect; thus, no statistical comparison or testing 
will be conducted against or between the monotherapy arms. 
Interim analyses will be conducted separately when the 24th patient enrolls into the nemvaleukin 
monotherapy arm and the 12th patient enrolls into the pembrolizumab monotherapy arm; these 
analyses will be conducted by an independent statistician. The interim analysis on the ORR will 
provide a statistical recommendation for early stopping due to futility. The pembrolizumab 
monotherapy arm (Arm 2) met its pre-specified futility criteria at the planned futility analysis 
and was closed to enrollment as of 31 Aug 2023, per the recommendation of the IDMC. 
The stopping boundary is summarized in Table 23. 
Table 23: 
Stopping Boundary for Interim Futility Analysis of Objective Response Rate 
in Monotherapy Arms 
Monotherapy Arm: 
Interim Analysis at: 
Recommend Stopping Enrollment if: 
Pembrolizumab 
Monotherapy Arm 
(closed as of 
31 Aug 2023) 
First 12 dosed patients 
0 or 1 response (confirmed PR or CR) 
Nemvaleukin 
Monotherapy Arm 
First 24 dosed patients  
0 response (confirmed or unconfirmed PR or 
CR or durable SD lasting for ≥3 months) 
CR=complete response, PR=partial response, SD=stable disease. 
If the futility criteria are met, further enrollment into the arm will stop; patients in the arm 
receiving benefit (SD or better) may remain on study until progression. Crossover to another 


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treatment arm is not allowed. (Note: all patients who progress at any time will be immediately 
discontinued from treatment; Section 7.5.1). 
There will be no type I error rate adjustment caused by this futility analysis, as the monotherapy 
arms are not included for any statistical comparisons. 
Interim Analysis of OS 
One planned efficacy interim analysis of OS will be performed when approximately 215 death 
events (at approximately 75% information fraction) are observed in the 2 arms (the Combination 
and the Chemotherapy arms). The Lan-DeMets O’Brien-Fleming alpha-spending function is 
constructed to implement group sequential boundaries to control the type I error rate. 
Table 24 summarizes the analysis strategies. If the actual number of OS events at the interim and 
final analyses differs from those specified in the table, the boundaries will be adjusted using the 
Lan-DeMets O’Brien-Fleming alpha-spending function accordingly. 
Table 24: 
Summary of Number of Events and Decision Guidance at the Planned 
Overall Survival Analyses 
Analysis 
Expected Number of Events at the Time of Analysis 
Efficacy Boundary 
p-valuea 
HR 
OS IA 
~215 OS events in the Combination and the 
Chemotherapy arms 
0.0096 
0.7265 
OS FA 
~286 OS events in the Combination and the 
Chemotherapy arms 
0.0221 
0.7882 
Abbreviations: FA=final analysis, HR=hazard ratio, IA=interim analysis, OS=overall survival 
a p-value (1-sided) is the nominal significance level for testing and will be used to claim crossing of a boundary. 
11.7. 
Subgroup Analysis 
Subgroup analyses relevant to baseline characteristics and disease will be performed (eg, prior 
treatments, ECOG status, biomarkers, stratification factors, age, region, race, disease stage, and 
number of prior lines of therapy). Details of these analyses and additional subgroup analyses will 
be described in the SAP. 


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13. 
APPENDICES 
13.1. 
Appendix 1: Contraception Definitions 
Woman of Childbearing Potential 
A woman is considered a WOCBP, ie, fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. (Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.) 
• WOCBP using highly effective methods of contraception are eligible to participate in 
this study. 
• WOCBP using unacceptable methods of contraception or effective methods of 
contraception are not eligible to participate in the study unless they switch to a highly 
effective method of contraception prior to their participation in the study. 
Postmenopausal Female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulation hormone level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal 
contraception or HRT. However, in the absence of 12 months of amenorrhea, 
confirmation with more than one follicle stimulating hormone measurement 
(>40 IU/L or mIU/mL) is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Sterilized Female 
Sterilized females are those who have undergone total hysterectomy and/or bilateral 
oophorectomy and/or bilateral salpingectomy. 
Highly Effective Methods of Contraception 
• Intrauterine device 
• Bilateral tubal occlusion 
• Vasectomized partner (provided that partner is the sole sexual partner of the study 
patient and that the vasectomized partner has received medical assessment of the 
surgical success) 
• Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
− Oral 
− Intravaginal 


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− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug 
− Oral 
− Injectable 
− Implantable 
• Sexual abstinence: sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the patient. 
Effective Methods of Contraception 
If genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the investigational drug, 
comparator, background therapy, or standard of care medications, effective methods of 
contraception (there may be a higher than 1% failure rate) are: 
• Double-barrier method (combination of male condom with either cap, diaphragm or 
sponge with spermicide) 
• Male or female condom, with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 
• Progestogen-only hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
Unacceptable methods of contraception are: 
• Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods) 
• Spermicides only 
• Withdrawal (coitus interruptus) 
• Lactational amenorrhea method 
• Use of female and male condoms together 
• Cap/diaphragm/sponge without spermicide and without condom 


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13.2. 
Appendix 2: New York Heart Association Heart Disease 
Classifications 
Table 25: 
New York Heart Association Heart Disease Classifications 
Class Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnea. 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, and/or dyspnea. 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, and/or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. 
If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: 
Lippincott Williams and Wilkins; 01 Mar 1994. 


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13.3. 
Appendix 3: Clinical Laboratory Assessments 
Table 26: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Coagulation 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cell count 
• 
Total and differential 
(absolute) white blood 
cell count 
• 
Note: absolute counts 
for neutrophils, 
lymphocytes, 
monocytes, and 
eosinophils 
• 
Platelet count 
• 
C-reactive protein 
General Chemistry 
• 
Albumin 
• 
Bicarbonate 
• 
Calcium 
• 
Chloride 
• 
CPK 
• 
Glucose 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
• 
Amylase 
• 
Lipase 
Renal Function Tests 
• 
BUN 
• 
Creatinine 
Liver Function Tests 
• 
ALT 
• 
ALK-P 
• 
AST 
• 
LDH 
• 
Total bilirubin 
Endocrine Testsa 
• 
Thyroid-stimulating 
hormone (TSH)b 
• 
ACTH 
• 
Total cortisol 
• 
Free T4 
• 
Total or free T3 
• 
Color and appearance 
• 
pH 
• 
Specific gravity 
• 
Ketones 
• 
Protein 
• 
Glucose 
• 
Bilirubin 
• 
Nitrites 
• 
Urobilinogen 
• 
Leukocytes 
• 
Leukocyte esterase 
• 
Occult blood 
• 
Microscopic 
examination of 
sediment, only if 
urinalysis dipstick 
results for blood, 
leukocytes or protein 
are abnormal (ie, 2+ 
or higher) 
• 
INR 
• 
aPTT 
ACTH=adrenocorticotropic hormone, ALK-P=alkaline phosphatase, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, AST=aspartate 
aminotransferase, BUN=blood urea nitrogen, CPK=creatine phosphokinase, INR=international normalized ratio, LDG=lactate dehydrogenase, 
T3=triidothyronine, T4=thyroxine 
a Endocrine tests will be performed for all patients at Screening. On-treatment endocrine tests are only applicable to Arm 1, 2, and 3. 
b If TSH result is abnormal, collect total T3 or free T3 and Free T4. 


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13.4. 
Appendix 4: Eastern Cooperative Oncology Group Status 
Table 27: 
Eastern Cooperative Oncology Group Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature (eg, light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: (Oken et al, 1982) 
 


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13.5. 
Appendix 5: COVID-19 Structured Risk Analysis 
13.5.1. 
COVID-19 Related Risks 
The objective of this appendix is to outline the protocol procedures that can be considered during 
the COVID-19 pandemic. 
In response to COVID-19, the FDA, the EMA, and local authorities have issued guidance to 
assist Sponsors during the pandemic. Compliance with the study protocol should be ensured to 
such an extent that an ongoing benefit-risk assessment for the clinical study and its participants is 
not compromised. 
The goal is to have the protocol followed in full and to minimize missing data, but where this is 
not possible due to COVID-19 (or another catastrophe), the site, in consultation with Mural and 
the IRB/EC, should assess alternative protocol procedures in a risk and benefit manner, leading 
with patient safety, personnel safety, study objectives, and considering local and regional 
requirements. 
The current COVID-19 pandemic can pose a challenge to the continuity of studies, the protection 
of study patients’ rights, and the safety and well-being of study staff. Such situations may 
necessitate, for example, quarantines (patient-imposed, institution-imposed, or 
government-imposed), site closures, travel restrictions, interruptions to the supply chain for study 
materials, or other considerations for the protection of clinical study patients and/or site 
personnel. Related challenges may lead to difficulties in performing protocol-specified 
procedures, administration of study drug(s), as well as adherence to site visits, 
laboratory/diagnostic testing, and/or disease assessment scheduling. 
Therefore, risk mitigation strategies will be evaluated on an ongoing basis for the duration of this 
study, or until there is a consensus that the period of the COVID-19 outbreak has been brought 
under control. Ongoing monitoring of the study will be performed in accordance with the 
Monitoring Plan, using risk-based monitoring and/or remote monitoring methods when needed in 
lieu of on-site monitoring. If the dynamics of the COVID-19 outbreak change in such a way that 
the safety of the study patients and study staff, or the integrity of the data collected during this 
study cannot be guaranteed, a temporary study hold may be implemented. 
13.5.2. 
Risk for Patients and Study Staff 
The risks of COVID-19 have not been fully established and there may be comorbidities, other 
than cancer itself that can put patients at higher risk. Investigators should use their medical 
judgement and current evidence and consult with Mural and their local IRB/EC at any time 
point, in order to determine the risks and benefits for each study patient to continue in the study 
as more information becomes known regarding the potential impact COVID-19 may have on 
study patients. 
Sites are recommended to follow institutional guidelines to prevent COVID-19 infections among 
study patients. 
In order to mitigate the possible increased risk associated with study participation during the 
COVID-19 pandemic, investigators should evaluate whether alternative methods for assessments 
(eg, phone contact, virtual visit/telemedicine, extension of visit windows, alternative location for 


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assessment, including local labs) can be implemented when necessary and feasible, in 
consultation with Mural and the IRB/EC to ensure patient safety. 
In the event of disruption to the conduct of the study during a pandemic/epidemic, the following 
alternative methods are available for study-related patient management; and where appropriate, 
protocol deviation will be documented and communicated to Mural and the IRB/EC according to 
local requirements: 
1. If at any time a patient is considered to be at risk, appropriate modification to the 
patient’s study schedule should be made. If needed, study treatment may be delayed, and 
re-treatment guidance should be followed as described in the protocol. If deemed 
necessary, study treatment should be discontinued, and study follow-up assessments 
should be conducted. 
2. If a scheduled visit cannot be conducted in person at the study site, it should be 
performed remotely/virtually or delayed until such time that on-site visits may be safely 
resumed. Upon remote contact, patients should be interviewed to collect clinical safety 
data. Patients should also be questioned regarding their general health status to fulfill 
physical examination requirements to the extent possible. 
3. Every effort should be made to adhere to protocol-specified laboratory and/or diagnostic 
assessments, including follow-up assessments. Safety laboratory assessments may be 
performed at a local laboratory closer to the patient, if needed. 
4. Sites are expected to comply with (S)AE reporting requirements as described in the 
protocol. (S)AEs as a result of, eg, COVID-19 infection while on study should be 
reported accordingly, and the event should be recorded as a separate AE. 
5. Key disease status and efficacy endpoint assessments should be performed if required and 
feasible. 
6. Study site representatives should inform the Sponsor regarding any locally imposed 
COVID-19 mitigations as soon as possible. 
7. If necessary, protocol deviations should be specified as being due to the 
pandemic/epidemic. 
8. Changes to study procedures, including missed study visits or a decision to discontinue 
study participation, should be documented in source notes and in the eCRF as advised by 
the Sponsor. 
Patients who volunteer to participate in this clinical study have a life-threatening disease and it is 
expected that this specific population may be offered the COVID-19 vaccine before or while 
being treated with study drug. Live vaccines are prohibited, and sites should follow the guidance 
provided in study entry-criteria, including prohibited and concomitant medication section of the 
protocol. 


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If a patient is offered a COVID-19 vaccine during participation in the clinical study, the 
following advice is offered to minimize unanticipated interactions with the study treatment (since 
it is unknown whether investigational product will affect the efficacy of the vaccine), as well as 
facilitate the ability to distinguish side effects potentially attributable to the vaccine vs those 
attributable to the study treatment: 
• It is recommended that the vaccine is not administered within 7 days prior to or 
3 days after study drug administration; however, when needed this window can be as 
short as ±3 days ie, for weekly dosing schedule for study treatment is applied. 
Regulatory guidance requires the Sponsor to continuously monitor for overall COVID-19 impact 
on achieving the objectives of the study and any changes (eg, interruption or discontinuation in 
patient recruitment, site monitoring, and audits) will be communicated to sites and to relevant 
health authorities according to local guidance. Modifications made to study conduct as a result of 
disruption(s) related to the COVID-19 pandemic/epidemic will be summarized in the Clinical 
Trial Report. 
This guidance is not intended to supersede any local or government requirements or the clinical 
judgement of the Investigator to protect the health and well-being of clinical study patients and 
site personnel. 
13.5.3. 
Impact of the Investigational Drug on COVID-19 
The impact of the study drug (nemvaleukin) on the susceptibility of study patients to the 
SARS-CoV-2 virus infection, effect on signs, symptoms, or complications are unknown at this 
time. Sites and patients will be made aware as further information becomes available. 


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13.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight 
Considerations 
13.6.1. 
Regulatory and Ethical Considerations 
This study will be conducted under ICH E6 GCP and all applicable regulatory requirements. To 
ensure data accuracy, completeness, and compliance, the study site should have processes in 
place for data review and quality control. Mural may also conduct monitoring and quality 
assurance audits. Please see Section 13.6.6.2 for details regarding the audit process. 
This study will be conducted in accordance with the IRB/EC-approved protocol, protocol 
amendments, ICF, IB, other relevant documents (eg, advertisements), and with the following 
applicable regulatory requirements to ensure data accuracy, completeness, and compliance: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• Applicable ICH GCP Guidelines and US CFR applicable to clinical studies 
• Applicable state, local, and federal laws and regulatory requirements 
Each clinical site’s IRB/EC must meet all relevant regulatory requirements. The study protocol, 
ICF, recruitment materials, and all patient materials will be submitted to the IRB/EC for review 
and approval. Written approval from the committee must be received by Mural before study 
drug(s) will be released to the Investigator. Approval of both the protocol and the consent form 
must be obtained before any patient is enrolled. Any amendment to the protocol will require 
review and approval by the IRB/EC before the changes are implemented to the study. In 
addition, all changes to the consent form will be IRB/EC-approved; a determination will be made 
regarding whether a new consent needs to be obtained from patients who provided consent, using 
a previously approved consent form. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC. 
• Submitting all protocol changes, deviations, and SAE reports to the IRB/EC 
according to local procedures. At a minimum, all SAEs requiring an investigational 
new drug safety report must be immediately reported. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, and all other applicable local 
regulations. 
• Forwarding all relevant correspondence from the IRB/EC to the Sponsor in a timely 
fashion. 


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13.6.2. 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
13.6.3. 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. A prospective patient is 
defined as a patient who have indicated in advance (before receiving the ICF) a wish to receive 
information about a possible participation in the study. Each prospective patient will receive an 
IRB/EC -approved ICF that summarizes the pertinent study information and will be given ample 
time to read the form and ask questions about the study. The Investigator (or authorized 
designee) at each study center will ensure that the patient (or the patient’s legal representative as 
applicable per regional requirements) is given full and adequate oral and written information 
about the nature, purpose, potential and possible risks and benefits of the study, and answer all 
questions regarding the study. The ICF will include information, as it becomes available, related 
to the use of nemvaleukin in relation to the SARS-CoV-2 virus (see Appendix 5 for further 
details). All information is to be provided in a language understandable to the patient and must 
not include any language that waives the patient’s legal rights. Prospective patients must be 
informed that their participation is voluntary and must also be informed of their right to 
withdraw consent without prejudice at any time during the study. The rights and welfare of the 
patients will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. 
If the patient chooses to participate, he or she must sign the ICF before any study-specific 
procedures are conducted. 
• Patients or their legally authorized representative will be required to sign an ICF that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/EC or study center. 
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. The time that informed consent is obtained must be documented. The 
Investigator must maintain the original signed ICF in the patient’s source documents. 
• A copy of the ICF(s) must be provided to the patient or the patient’s legally 
authorized representative (as applicable per regional requirements). 
• Significant changes to the protocol or product safety information may require a 
revision of the ICF, which must be reviewed and approved by the IRB/EC, and then 
signed by all applicable study patients. Patients must be re-consented to the most 
current version of the ICF(s) during their participation in the study. 


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• A patient who is rescreened is not required to sign another ICF if the rescreening 
occurs within 14 days from the previous ICF signature date. 
All candidate patients will be informed of their rights to privacy and will be made aware that the 
study data will be submitted to Mural, the IRB/EC, the CRO, if applicable, and to regulatory 
authorities for review and evaluation for the duration of the study and until the project has been 
approved for marketing or is withdrawn from investigation. They will also be informed that the 
study monitors may inspect their medical records to verify the accuracy and completeness of the 
study records and results. 
If circumstances occur that are beyond the control of patients or sites (ie, states of emergency 
including natural disasters, public health mandates, etc), and the resultant changes to study 
processes require written informed consent from patients, alternative informed consent processes 
can be considered, in consultation with the sites’ IRB/EC. 
13.6.4. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to Mural that he or she will maintain in 
confidence information furnished to him or her by Mural and will divulge such information to 
his or her respective IRB/EC under an appropriate understanding of confidentiality with such 
board. All data will be considered the sole property of Mural. Please refer to the CSA for details. 
Data generated in this study are proprietary information that are the sole property of Mural. 
Results of the study are to be held in confidence by both the Investigators and the Sponsor. 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
• Essential documents should be retained for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required 
by the applicable regulatory requirements or by the terms of the CSA. It is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. No records may be transferred to another 
location or party without written notification to the Sponsor. 
• Patients’ medical files should be retained in accordance with the applicable 
legislation and in accordance with the maximum period of time permitted by the 
hospital, institution, or private practice. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 
13.6.5. 
Committees Structure 
The Investigator must obtain IRB/EC approval for the investigation. Initial IRB/EC approval, as 
well as all materials approved by the IRB/EC for this study, including the ICF and recruitment 
materials, must be maintained by the Investigator and made available for inspection. 


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13.6.6. 
Data Quality Assurance 
13.6.6.1. Study Monitoring 
Mural or its representative will be allowed to conduct site visits to the investigational facilities 
for the purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
Monitor to inspect the drug storage area, study drug stocks, drug accountability records, patient 
charts and source documents, and other records relative to study conduct. 
The investigational site will provide direct access to all study-related sites, source 
data/documents, and reports for the purpose of study-related monitoring, audits, and IRB/EC 
review by the Sponsor, and inspection by local and regulatory authorities. 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by a Mural Monitor or designee. 
Clinical site monitoring is conducted to ensure that the rights and well-being of study patients are 
protected, that the reported study data are accurate, complete, and verifiable, and that the conduct 
of the study is in compliance with the currently approved protocol/amendment(s), with 
ICH GCP, and with applicable regulatory requirements. Monitoring of this study will be 
performed by a Mural Monitor and according to the Study Clinical Monitoring Plan. The 
Clinical Monitoring Plan describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
13.6.6.2. Audits and Inspections 
Independent audits will be conducted by the Sponsor to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the Clinical 
Monitoring Plan. 
By signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of Mural, a regulatory 
authority, and/or an IRB/EC may visit the site to perform audits or inspections, including all 
study-related sites (ie, the drug storage area, study drug stocks, drug accountability records, 
patient charts and source documents, and other records relative to study conduct). The purpose of 
a Mural audit or inspection is to systematically and independently examine all study-related 
activities and documents (eg, laboratory reports, x-rays, workbooks, patients’ medical records) to 
determine whether these activities were conducted, and data recorded, analyzed, and accurately 
reported, according to the protocol, GCP guidelines of the ICH, and any applicable regulatory 
requirements. The auditor should verify that source documents and study records are accurate, 
complete, timely, and maintained. 
The Investigator should contact Mural immediately if contacted by a regulatory agency regarding 
an inspection. 
13.6.7. 
Source Documents 
An overview of study data handling and recordkeeping procedures and restrictions is provided 
here; please refer to the CSA for further details. 


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This study will use eCRFs for capturing data. All entries, corrections, and alterations will be 
made by the Investigator or other authorized study personnel. All data entries will be verified for 
accuracy and correctness by independent monitors. The EDC system maintains a full audit trail. 
A paper copy of all laboratory reports will remain with the source documents at the study site. 
All electronic source data collected outside of the eCRF, such as central laboratory data, will be 
transferred directly to EDC or directly to Mural for incorporation into the final datasets. 
All eCRF data must be based on source documents or approved to be the original data (ie, data 
directly reported on the eCRF). All eCRFs will be completed by the clinic staff prior to review 
by the Mural Monitor or designated representative. 
The Mural Monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF. 
Changes to study visit schedules, missed visits, treatment discontinuations, or patient 
discontinuations from study due to rare circumstances beyond the patient’s or site’s control 
(ie, states of emergency including natural disasters, public health mandates, etc) should be 
captured in the eCRF, to explain the reason for the missing data. 
13.6.8. 
Study and Site Closure 
The Sponsor may terminate the entire study or a single study center at any time for safety, 
administrative reasons, or other reasons. 
13.6.9. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that are the sole property of Mural. 
Results of the study are to be held in confidence by both the Investigators and the Sponsor. 
Please refer to the CSA for details on the procedures for publishing and presenting data. 
13.6.10. 
Major Protocol Deviations 
Sites will report protocol deviations to the Sponsor and to the IRB/EC per IRB/EC reporting 
requirements. During data cleaning and during review of data listings, CRO and Sponsor 
representatives (from data management, drug safety, statistical programming, biostatistics, 
translational medicine, and/or the Medical Monitor) may identify additional deviations from the 
protocol. Deviations may also be identified through auditing or risk monitoring activities. All 
deviations will be collected in a deviation log. 
Deviations will be reviewed by Sponsor representatives in order to identify (1) any trends with 
site compliance, quality of data, and/or patient safety issues, (2) promptly assess areas of 
correction, re-training, and re-evaluation at the site and/or to the program, (3) identify the major 
protocol deviations, and (4) assess the need for protocol improvements and/or site training for 
the current or future studies. 
Deviations will be categorized and characterized as major or minor in accord with a protocol 
deviation plan. Major deviations will be reported to IRB/EC and to the Sponsor’s Biostatistics 
and Medical Writing groups for analysis and reporting in the clinical study report. 
Major deviations include, but are not limited to, those that involve fraud or misconduct, affect to 
a significant degree the safety and rights of a patient or the reliability and robustness of the data 


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generated, or confound interpretation of the primary study assessment. Any decision by the 
Sponsor to close a site due to non-compliance will also be reported to the applicable regulatory 
authorities. 

SAP_001.pdf: 
Mural Oncology, Inc. 
Statistical Analysis Plan ALKS 4230-007 v3.0 
 
1 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
ALKS 4230-007 
 
Study Title: 
A Phase 3, Multicenter, Open-Label, Randomized Study of 
Nemvaleukin Alfa in Combination with Pembrolizumab Versus 
Investigator’s Choice Chemotherapy in Patients with Platinum-Resistant 
Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 
(ARTISTRY-7) 
Document Date: 
Version 3.0 
19 Aug 2024 
Version 2.0 
05 Feb 2024 
 
Version 1.0 
16 Mar 2023 
Based on: 
ALKS 4230-007 Protocol v5.0, dated 31 Jan 2024 
Sponsor: 
Mural Oncology, Inc. 
852 Winter Street 
Waltham, MA 02451 
USA 
 
CONFIDENTIAL 
Information and data in this document contain trade secrets and privileged or confidential 
information, which is the property of Mural Oncology, Inc. No person is authorized to make it 
public without the written permission of Mural Oncology, Inc. These restrictions or disclosures 
will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. This study is being conducted in compliance with good clinical practice, including 
the archiving of essential documents. 
 
 




Mural Oncology, Inc. 
Statistical Analysis Plan ALKS 4230-007 v3.0 
 
3 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
VERSION HISTORY ...................................................................................................9 
2. 
INTRODUCTION ......................................................................................................10 
2.1. 
Overall Study Design ..................................................................................................10 
2.2. 
Study Objectives and Endpoints .................................................................................12 
3. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION .......................13 
4. 
GENERAL ANALYSIS DEFINITIONS ...................................................................14 
4.1. 
Visit Windows ............................................................................................................14 
4.2. 
Analysis Population ....................................................................................................14 
4.2.1. 
Intent-to-Treat Population ..........................................................................................14 
4.2.2. 
Safety Population ........................................................................................................14 
4.2.3. 
Pharmacokinetic (PK) Population ..............................................................................15 
4.2.4. 
Pharmacodynamic Population ....................................................................................15 
4.3. 
Definition of Baseline .................................................................................................15 
4.4. 
Subgroup Analyses .....................................................................................................15 
4.5. 
General Analysis Methods ..........................................................................................16 
4.6. 
Pooling of Centers ......................................................................................................17 
4.7. 
Multiple Comparisons/Multiplicity ............................................................................17 
5. 
SUBJECT INFORMATION ......................................................................................17 
5.1. 
Disposition Information ..............................................................................................17 
5.2. 
Demographics and Baseline Characteristics ...............................................................17 
5.3. 
Protocol Deviations ....................................................................................................17 
5.4. 
Medical History ..........................................................................................................18 
5.5. 
Prior and Concomitant Medications ...........................................................................18 
5.6. 
Prior and Subsequent Anticancer Therapy .................................................................18 
5.7. 
Treatment Exposure ....................................................................................................18 
6. 
EFFICACY ANALYSES ...........................................................................................19 
6.1. 
General Considerations ...............................................................................................19 
6.2. 
Analysis of the Primary Endpoint...............................................................................19 
6.2.1. 
Sensitivity Analyses of the Primary Endpoint ............................................................21 


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6.3. 
Analysis of Secondary Endpoints ...............................................................................21 
6.4. 
Analysis for Exploratory Efficacy Endpoints .............................................................26 
7. 
SAFETY ANALYSIS ................................................................................................26 
7.1. 
General Considerations ...............................................................................................26 
7.2. 
Adverse Events ...........................................................................................................26 
7.2.1. 
Adverse Events of Special Interest .............................................................................28 
7.2.2. 
Death ...........................................................................................................................28 
7.3. 
Clinical Laboratory Parameters ..................................................................................29 
7.4. 
Vital Signs and ECG ...................................................................................................32 
7.4.1. 
Vital Signs ..................................................................................................................32 
7.4.2. 
Electrocardiograms .....................................................................................................32 
7.5. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .........................32 
7.6. 
Left Ventricular Ejection Fraction ..............................................................................33 
8. 
OTHER EXPLORATORY ANALYSES ...................................................................33 
8.1. 
Health-Related Quality of Life Analyses ...................................................................33 
8.2. 
Pharmacokinetic/ Pharmacodynamic Analyses ..........................................................35 
8.2.1. 
Pharmacokinetic Analyses ..........................................................................................35 
8.2.2. 
Blood Pharmacodynamic Analyses ............................................................................35 
8.2.3. 
Tumor Tissue Pharmacodynamic Analyses ................................................................36 
8.3. 
Immunogenicity Analyses ..........................................................................................36 
9. 
INTERIM ANALYSES ..............................................................................................36 
9.1. 
Interim Futility Analysis of ORR in Each Monotherapy Arm ...................................37 
9.2. 
Interim Efficacy Analysis of OS .................................................................................37 
9.3. 
Blinding and Independent Data Monitoring Committee ............................................38 
10. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ...............................................................................................................38 
11. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........38 
11.1. 
Analysis Visit Windows .............................................................................................38 
11.2. 
Safety Data Handling ..................................................................................................39 
11.3. 
Handling of Partial Dates of Concomitant Medication ..............................................39 
11.4. 
Reporting Precision ....................................................................................................40 
12. 
REFERENCES ...........................................................................................................40 
13. 
APPENDIX.................................................................................................................41 


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13.1. 
Extended Time Without an Evaluable Tumor Assessment ........................................41 
 
LIST OF TABLES 
Table 1: 
Abbreviations ................................................................................................................6 
Table 2 
Version History Summary ............................................................................................9 
Table 3: 
Censoring Rule for Progression-free Survival ............................................................22 
Table 4: 
Clinical Laboratory Assessments ...............................................................................30 
Table 5: 
Eastern Cooperative Oncology Group Performance Status ........................................32 
Table 6: 
Criteria for Best Overall HRQoL Response ...............................................................34 
Table 7: 
Pre-Defined Thresholds for Meaningful HRQoL Change ..........................................34 
Table 8: 
Stopping Boundary for Interim Futility Analysis of ORR in Monotherapy 
Arms ...........................................................................................................................37 
Table 9: 
Summary of Number of Events and Decision Guidance at the Planned OS 
Analyses ......................................................................................................................38 
Table 10: Degree of Precision .....................................................................................................40 
Table 11: Determination of ≥2 Missed Tumor Assessments ......................................................41 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design Schematic ................................................................................11 
 


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LIST OF ABBREVIATIONS 
Table 1: 
Abbreviations 
Abbreviation Definition 
ACTH 
Adrenocorticotropic hormone 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ALK-P 
alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate Aminotransferase  
AUC 
area under the curve 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA 
Cancer antigen - 
CI 
Confidence Interval 
CLS 
Capillary Leak Syndrome 
CMH 
Cochran-Mantel-Haenszel 
CPK 
Creatine phosphokinase 
CPS 
Combined Positive Scores  
CR 
Complete Response 
CRS 
Cytokine Release Syndrome 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
EWB 
emotional well-being 


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Abbreviation Definition 
eCRF 
electronic case report form 
ED-5Q-5L 
EuroQol 5 Dimension 5-Level 
FA 
Final analysis 
FACT-O 
Functional Assessment of Cancer Therapy- Ovarian 
FOSI 
FACT Ovarian Symptom Index 
FWB 
functional well-being 
GCIG 
Gynecologic Cancer InterGroup 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IA 
Interim analysis 
IDMC 
independent data monitoring committee 
IL 
Interleukin 
INR 
International normalized ratio 
irAEs 
Immune-related Adverse Events 
IRR 
infusion-related reaction 
ITT 
intent-to-treat 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
N/A 
Not Applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NK 
Natural Killer [Cells] 
ORR 
Objective Response Rate 
OS 
Overall survival 
PARPi 
poly adenosine diphosphate-ribose polymerase inhibitors 
PCS 
Potentially clinically significant 
PD 
Progressive Disease 
PD-L1 
Programmed Death Ligand-1 
PK 
Pharmacokinetic(s) 


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Abbreviation Definition 
PFS 
Progression-Free Survival 
PLD 
Pegylated Liposomal Doxorubicin 
PR 
Partial Response 
PRO 
Patient-Reported Outcome 
PT 
Preferred Term 
PWB 
physical well-being 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMST 
restricted mean survival time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SWB 
social/family well-being 
SOC 
System Organ Class 
T3 
Triiodothyronine  
T4 
Free thyroxine 
TBILI 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid-stimulating hormone  
TTR 
Time to Response 
TOI 
Trial Outcome Index 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
 


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1. 
VERSION HISTORY 
This statistical analysis plan (SAP) for Study ALKS 4230-007 is based on the study protocol 
version 5.0 (dated 31 Jan 2024). 
Table 2 
Version History Summary 
Version Version Date 
Summary of Changes 
Rationale 
3.0 
19 Aug 2024 
• Add definition of clinical 
data cut-off 
• Clarify definition of 
baseline to include 
handling of unscheduled 
assessments 
• Reduce number of 
subgroup analyses  
• Update duration of 
exposure algorithm to align 
with definition of cycle 
• Clarify algorithm to 
determine date of last 
contact for OS 
• Added primary estimand 
for OS, PFS, and ORR 
• Clarify safety summaries to 
align with ICH 
requirements 
• Added analysis of left 
ventricular ejection fraction 
• Clarify timing of sponsor 
unblinding 
• Correct typos 
• Align analysis within the program 
• Add estimand framework to align 
with ICH E9(R1) 
2.0 
05 Feb 2024 
• Updated enrollment details 
to reflect increase in 
enrollment for Arms 1 and 
4 
• Update primary endpoint 
and associated study design 
and analysis details 
(sample size, interim 
• Update Sponsor to Mural 
Oncology, Inc 
• Align with protocol amendment  


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analysis, sensitivity 
analyses) from OS to PFS 
• Update subgroup analyses 
• Non substantial updates to 
clarify analyses  
1.0 
16 Mar 2023 
Not applicable (N/A) 
N/A 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical methods and data 
presentation to be used for analyzing and reporting efficacy and safety data for Study ALKS 
4230-007. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition or its analysis will be reflected in a protocol 
amendment.  
The primary analysis will include data up to a clinical cut-off date which is determined by the 
number of events (deaths).  The cut-off date is determined once a data extract (before database 
lock) is available which indicates that the required number of events have occurred.  Due to data 
cleaning activities, the final number of events may deviate from the planned number.  The data 
cut-off date will not be adjusted retrospectively in this case. 
2.1. 
Overall Study Design 
This is a Phase 3, multicenter, open-label, randomized study of nemvaleukin in combination with 
pembrolizumab versus protocol-specific Investigator’s choice chemotherapy in patients with 
platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. 
Per the original study design, patients were centrally allocated in a randomized fashion (3:1:1:3) 
to receive either: 
• Arm 1: nemvaleukin and pembrolizumab combination therapy 
• Arm 2: pembrolizumab monotherapy (closed) 
• Arm 3: nemvaleukin monotherapy (closed) 
• Arm 4: Investigator’s choice chemotherapy. Options for protocol-specific 
Investigator’s choice chemotherapy include one of the following: pegylated liposomal 
doxorubicin (PLD), paclitaxel, topotecan, or gemcitabine. The Investigator will pre-
select the Investigator’s choice treatment before the randomization of each patient. 
The pembrolizumab monotherapy arm (Arm 2) met its pre-specified futility criteria at the 
planned futility analysis and was closed to enrollment as of 31 Aug 2023, per the 
recommendation of the independent data monitoring committee (IDMC). The nemvaleukin 
monotherapy arm (Arm 3) did not meet its prespecified futility criteria at the planned futility 
analysis and the IDMC recommended continuation. Under protocol version 4.0, the nemvaleukin 
monotherapy arm (Arm 3) reached its intended enrollment and thus closed. Because no changes 
have been made to the objectives related to Arm 3 in protocol version 5.0, the Arm 3 number of 


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patients was not recalculated. Therefore, in protocol version 5.0, eligible patients will continue to 
be enrolled in the remaining 2 arms and will be centrally allocated with a randomization ratio of 
1:1 to the Combination and Chemotherapy arms (Arm 1 and Arm 4, respectively). 
To ensure equal distribution of prognostic factors in the study arms, patients will be stratified 
according to the following parameters: 
• Programmed Death Ligand-1 (PD-L1) status (immunohistochemistry combined 
positive scores [CPS] ≥10 vs CPS <10) 
• Histological subtype (high-grade serous vs non-high-grade serous) 
• Investigator’s choice chemotherapy (paclitaxel vs other chemotherapies) 
Response assessments will include computed tomography (CT) scans and/or magnetic resonance 
imaging (MRI) every 6 weeks (Year 1) and every 12 weeks (Year 2+), with mandatory relevant 
imaging of the chest, abdomen, and/or pelvis. Brain imaging should be performed when there is 
a history of/suspicion of brain metastasis. Response and progression free survival (PFS) will be 
evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines. For 
patients who complete treatment or discontinue treatment for reasons other than disease 
progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 6 weeks (Year 1 from start of treatment) or every 12 weeks (Years 2+ 
from start of treatment) until (1) the assessment of progressive disease, (2) the initiation of new 
anticancer therapy(ies), (3) withdrawal of consent, (4) death, or (5) end of study, whichever 
occurs first. 
An overall schematic of the study design is provided in Figure 1. 
Figure 1: 
Overall Study Design Schematic 
 
Abbreviations: EOT=end of treatment; IV=intravenous; PLD=pegylated liposomal doxorubicin. 
Note: As of protocol version 5.0, the pembrolizumab and nemvaleukin monotherapy arms (Arm 2 and Arm 3, 
respectively) are closed to enrollment. 
*Treatment with pembrolizumab (Arms 1 and 2) is allowed for up to a maximum of 35 cycles (approximately 
2 years). 
**Alternatively, topotecan may be administered at 1.25 mg/m2 on Days 1 through 5 of 21-day cycles. 


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2.2. 
Study Objectives and Endpoints 
The study objectives and corresponding endpoints are summarized below. 
Study Objectives 
Study Endpoints 
Primary Objective: 
• 
To evaluate the overall survival (OS) of 
nemvaleukin in combination with 
pembrolizumab as compared with 
chemotherapy in patients with platinum 
resistant ovarian cancer 
Primary Endpoint: 
• 
OS 
Secondary Objectives: 
• 
To evaluate the antitumor activity of 
nemvaleukin in combination with 
pembrolizumab as compared with 
chemotherapy 
• 
To evaluate the safety of nemvaleukin in 
combination with pembrolizumab as 
compared with chemotherapy 
Secondary Endpoints: 
• 
Progression free survival (PFS) as assessed 
by Investigator, based on Response 
Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 
• 
Objective response rate (ORR) as assessed 
by Investigator, based on RECIST v1.1 
• 
Disease control rate (DCR), duration of 
response (DOR), and time to response 
(TTR) as assessed by Investigator, based on 
RECIST v1.1 
• 
Cancer antigen (CA)-125 response as 
defined by the Gynecologic Cancer 
InterGroup (GCIG) 
• 
Safety as assessed by treatment-emergent 
AEs (TEAEs), clinical laboratory 
parameters, vital signs, and 
electrocardiograms (ECGs) 


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Study Objectives 
Study Endpoints 
Exploratory Objectives: 
• 
To evaluate the antitumor activity of 
pembrolizumab monotherapy; to evaluate the 
antitumor activity of nemvaleukin 
monotherapy 
• 
To evaluate health-related quality of life 
(HRQoL) 
• 
To determine if any baseline or changes in 
parameters in tumor tissue and/or peripheral 
blood may correlate to response to treatment 
with nemvaleukin in combination with 
pembrolizumab 
• 
To evaluate the pharmacokinetics (PK), 
immunogenicity, and pharmacodynamic 
effects of nemvaleukin and/or 
pembrolizumab in this treatment regimen 
Exploratory Endpoints: 
• 
PFS, ORR, DOR, TTR, and OS of the 
monotherapy arms as assessed by 
Investigator, based on RECIST v1.1 
• 
HRQoL as assessed by the following patient-
reported outcome (PRO) instruments: the 
Functional Assessment of Cancer Therapy – 
Ovarian (FACT-O) questionnaire and the 
EuroQol 5 Dimension 5-Level (EQ-5D-5L) 
questionnaire 
• 
Pretreatment levels, on-treatment levels, 
and/or changes from pretreatment levels of 
the following parameters (in tumor 
specimens and/or peripheral blood): 
o Combined positive score (CPS) of 
programmed death ligand-1 (PD-L1), 
mutational burden of tumors, and other 
relevant genetic and non-genetic 
predictive markers (eg, homologous 
recombination repair pathway deficiency, 
breast cancer gene mutation) 
o Serum concentrations of nemvaleukin 
(and pembrolizumab as appropriate) 
o Presence of anti-nemvaleukin antibodies 
(and anti-pembrolizumab antibodies as 
appropriate) in serum 
o Leukocytes including, but not limited to, 
circulating CD8+ T cells, Tregs, and 
natural killer (NK) cells 
o Serum concentrations of interferon-γ, 
interleukin (IL)-6, and other soluble 
proteins 
3. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION 
The Chemotherapy Arm is considered the comparator arm in this study; the antitumor activity of 
nemvaleukin in combination with pembrolizumab as compared to that of Investigator’s choice 
chemotherapy in patients with platinum-resistant ovarian cancer will be evaluated. 
The primary endpoint was changed from PFS to OS in protocol version 5.0; therefore, the 
sample size was recalculated based on OS assumptions. 
Approximately 366 subjects are planned to be randomized in a 1:1 ratio into the Combination 
and the Chemotherapy arms (Arm 1 and Arm 4, respectively). It is expected that approximately 
286 deaths will have been observed between the Combination and the Chemotherapy arms at the 


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final OS analysis. The study has an approximate 85% power to detect an OS hazard ratio of 0.7 
(the Combination arm vs the Chemotherapy arm) at an alpha level of 2.5% (one-sided). 
The sample size calculation is based on the following assumptions: 
1. 2.5% alpha is allocated to the OS endpoint; 
2. overall survival follows an exponential distribution with a median of 10 months and 
14.3 months in the Chemotherapy arm and Combination arm, respectively; 
3. the hazard ratio is 0.7, corresponding to a 4.3 month increase in the median OS; 
4. an enrollment period of 25 months; and 
5. a yearly dropout rate of 5%. 
Under protocol version 5.0, approximately 450 patients are planned, including approximately 
366 patients planned across Arm 1 and Arm 4 (approximately 183 patients in each arm). Under 
protocol version 5.0, no additional patients will be enrolled in the pembrolizumab monotherapy 
or nemvaleukin monotherapy arms (Arm 2 and Arm 3, respectively). 
One planned efficacy interim analysis of OS will be performed when approximately 215 death 
events (approximately 75% information fraction) are observed in the two arms (the Combination 
and the Chemotherapy arms). The Lan-DeMets O’Brien-Fleming alpha spending function is 
constructed to implement group sequential boundaries to control the type I error rate. 
The sample size and power calculations were performed in the software R (package “gsDesign”). 
The monotherapy arms (either pembrolizumab alone or nemvaleukin alone) are included for 
reference only to examine component effect, and no statistical comparison or testing will be 
conducted against or between these arms. 
4. 
GENERAL ANALYSIS DEFINITIONS 
4.1. 
Visit Windows 
Nominal visit days will be used in the analysis, unless specified otherwise. 
4.2. 
Analysis Population 
4.2.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population will include all randomized patients regardless of the study 
drugs (nemvaleukin, pembrolizumab, or Investigator’s choice chemotherapy) received. 
4.2.2. 
Safety Population 
The Safety Population will include all randomized patients who received any exposure to 
nemvaleukin, pembrolizumab, or Investigator’s choice chemotherapy. 


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4.2.3. 
Pharmacokinetic (PK) Population 
The PK Population will consist of all patients who received at least 1 dose of nemvaleukin or 
pembrolizumab and have at least 1 measurable serum concentration of nemvaleukin or 
pembrolizumab at any scheduled PK timepoint. 
4.2.4. 
Pharmacodynamic Population 
The Pharmacodynamic Population will consist of all patients who received at least 1 dose of 
nemvaleukin, pembrolizumab, or Investigator’s choice chemotherapy and have at least 1 
available post-baseline pharmacodynamic measurement. 
4.3. 
Definition of Baseline 
Baseline is defined as the last non-missing value prior to patient’s first dose of study drug. 
If an assessment is planned to be performed prior to the first dose of study treatment and the 
assessment is performed on the same day as the first dose of study treatment, it will be assumed 
that it was performed prior to study treatment administration, unless time of assessment is 
collected.  
Unscheduled assessment will be used in the determination of baseline. However, if time is 
missing, an unscheduled assessment on study day 1 will be considered to have been obtained 
after the study drug administration. For patients without central laboratory results at baseline,  
local laboratory results can be used in the determination of baseline. 
Study drug is defined as nemvaleukin and/or pembrolizumab, or Investigator’s choice 
chemotherapy. 
4.4. 
Subgroup Analyses 
Subgroup analyses will be performed based on the subjects in the Combination and the 
Chemotherapy arms (Arm 1 and Arm 4, respectively) for the primary endpoint of OS to assess 
the consistency of treatment effect across potential or expected prognostic factors. If there are 
too few OS events in a particular subgroup, ie, <20 events per subgroup level, only descriptive 
summaries will be provided. Combining relevant subgroup levels may be considered if 
necessary. 
The subgroups include, but are not limited to, the following: 
1. Demographic subgroups 
a. Region: North America (NA) and Europe (EU) vs Rest of the World (ROW) 
b. Age: <65 vs ≥65 
c. Race: White vs All Others 
2. Biomarker subgroups 
a. Programmed death-ligand 1 (PD-L1) expression at baseline: combined positive score 
(CPS) <10 vs ≥10 
3. Tumor burden subgroups 
a. Visceral vs non-visceral disease 


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b. Ascites at screening: yes vs no 
4. Baseline disease characteristics subgroups 
a. Disease Stage at diagnosis: Stage I-III vs Stage IV 
b. Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status: 0 vs 1 
c. Prior poly adenosine diphosphate-ribose polymerase inhibitors (PARPi): yes vs no 
d. Number of prior anticancer therapies: ≤3 vs ≥4 
e. Number of prior anticancer therapies in platinum resistant setting: ≤3 vs ≥4 
Platinum resistance is defined as either (1) primary platinum resistance: disease 
progression 90-180 days following the end of last administered dose of the first 
line or initial platinum therapy and received at least 4 cycles of platinum ; or (2) 
secondary platinum resistance: disease progression within 180 days following the 
end of last administered dose of platinum therapy beyond first-line setting; or (3) 
platinum refractory: lack of response followed by disease progression while 
receiving the most recent platinum-based therapy (ie, beyond initial therapy). 
f. Investigator’s choice of chemotherapy per randomization stratification factor: 
Paclitaxel vs Other 
g. Primary platinum-free interval: <=180 days vs  >180 days 
Primary platinum-free interval is defined as the time from the end date of last 
dose of platinum therapy to the date of progression following the initial or first 
line of platinum therapy.   
h. Platinum response to last platinum therapy: resistant vs refractory 
i. Histology type: high-grade serous vs non-high-grade serous (ie, endometrioid 
carcinoma, clear cell carcinoma, others) 
For each subgroup, hazard ratios (HRs) and associated confidence intervals (CIs) will be 
calculated from an unstratified Cox proportional hazards model for OS. The HRs and two-sided 
95% CIs will be presented on a forest plot including the HR and two-sided 95% CI for the 
overall group. Summaries of the number and percentage of patients experiencing an OS event for 
each subgroup will be provided along with the median OS by treatment arms for the 
Combination and the Chemotherapy arms (Arm 1 and Arm 4, respectively). 
4.5. 
General Analysis Methods 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables and number and percentage of patients in each category for 
categorical variables) will be provided for evaluated variables by treatment arms. Study drug is 
defined as nemvaleukin and/or pembrolizumab, or Investigator’s choice chemotherapy. 
Missing data will not be imputed unless otherwise specified. 
Multiplicity adjustment will not be applied to sensitivity analyses. The Chemotherapy Arm 
consists of multiple agents depending on the Investigator’s choice; all these agents together will 
be considered as one Chemotherapy Arm. The statistical comparison or testing will only be 
conducted between the Combination Arm and the Chemotherapy Arm. No statistical comparison 
or testing will be conducted against or between the monotherapy arms. 


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4.6. 
Pooling of Centers 
Data from all study sites will be combined for analysis. Subgroup analysis based on region (NA 
and EU vs ROW) will be conducted. No analysis for each site is planned. 
4.7. 
Multiple Comparisons/Multiplicity 
The overall type I error for this study is strongly controlled at 2.5% (one-sided), fully allocated to 
OS. The statistical comparison is only performed between the Combination and Chemotherapy 
arms. 
The Lan-DeMets O’Brien-Fleming alpha spending function is constructed to implement group 
sequential boundaries for OS hypothesis testing to control the type I error. 
Efficacy boundaries are based on the assigned type I error rate and the projected number of 
events at study milestones. The actual boundaries will be determined from the actual number of 
events at the time of the specified interim analysis using the alpha spending function. 
There will be no type I error rate adjustment for the interim futility analysis performed for each 
of the monotherapy arms since the monotherapy arms are not included for any statistical 
comparisons. 
5. 
SUBJECT INFORMATION 
The subject information analyses will be based on the ITT Population unless otherwise specified. 
5.1. 
Disposition Information 
The number and percentage of patients who discontinued the treatment and the reasons for 
treatment discontinuation will be summarized. 
The number and percentage of patients who discontinued the study and the reasons for study 
discontinuation will be also summarized. 
5.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics such as age, race, ethnicity, weight, height, body mass 
index (BMI), body surface area (BSA), and Eastern Cooperative Oncology Group (ECOG) status 
will be summarized with descriptive statistics for the ITT population. 
BSA will be calculated based on the Du Bois formula as follows: BSA (m2) = weight (kg)0.425 × 
height (cm)0.725 × 0.007184. 
5.3. 
Protocol Deviations 
Protocol deviations collected during the study conduct will be categorized and characterized as 
reportable or non-reportable in accordance with the protocol deviation plan. 
Reportable deviations will be summarized and assessed by treatment arms and a supportive 
listing will be provided.  


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5.4. 
Medical History 
Medical history information will be coded and summarized for the ITT Population using the 
most recent version of Medical Dictionary for Regulatory Activities (MedDRA). 
Cancer disease history data will be summarized with descriptive statistics for the ITT population. 
5.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized for the ITT population using the World 
Health Organization-Anatomical Therapeutic Chemical classification system. Prior medications 
are defined as medications started and ended prior to the first dose of study drug. Concomitant 
medications are defined as medications, other than study drug, either started prior to first dose 
and ongoing at the first dose, or started on or after the first dose of study drug. For the summary 
tables, if a subject has taken a prior or concomitant medication more than once, the subject will 
be counted only once for the medication. 
5.6. 
Prior and Subsequent Anticancer Therapy 
The following data are collected in the electronic case report form (eCRF) for prior anticancer 
therapy for disease of interest and the new anticancer therapy following study treatment 
respectively: Name of drug (and/or class), Start and Stop date, Progression date, Best response, 
and Reasons for discontinuation. 
Prior anticancer therapy for disease of interest and the subsequent anticancer therapy will be 
summarized separately. 
5.7. 
Treatment Exposure 
The treatment exposure of study drug (eg, duration of exposure, number of treatment cycles, 
number of infusions for each cycle, cumulative dose received, relative dose intensity, and missed 
doses) will be summarized for the Safety Population. 
Duration of exposure (weeks) is calculated as (last dose – first dose date + d) ÷ 7, where d is 1 if 
the participant discontinues study prior to end of the last cycle. For nemvaleukin d is 17. For 
pembrolizumab d is 21. For PLD, paclitaxel, topotecan, or gemcitabine d is 28, 7, 14, and 14 
respectively. 
Relative dose intensity (%) is calculated as 100 × [total dose received (μg/kg or mg or mg/m2) ÷ 
total protocol planned dose (μg/kg or mg or mg/m2)]. To calculate BSA based on the Du Bois 
formula and the actual dose (μg/kg or mg/m2) in each visit, the weight measured at the first 
dosing of each cycle will be used unless there is a dose adjustment in which case the weight 
measured on the dosing date will be used. The dose of nemvaleukin should be adjusted if the 
patient’s weight changes by >10% since the last time the dose was calculated or adjusted. If the 
weight was missing, the last observed weight from previous visit(s) will be carried forward. 


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6. 
EFFICACY ANALYSES 
6.1. 
General Considerations 
Antitumor activity and efficacy analyses will be summarized based on the ITT Population, unless 
specified otherwise. 
Analysis of antitumor outcomes (including ORR, DCR, DOR, PFS, and TTR) will be performed 
based on both Investigator review and central review of the radiographic measurements, 
respectively, as defined according to RECIST v1.1. The main analysis will be based on 
investigator assessment and sensitivity analysis will be based on central assessment. 
The stratification factors used for randomization (i.e. as entered into the Randomization and Trial 
Supply Management system) will be applied to all stratified analyses, in particular, the stratified 
log-rank test (weighted or unweighted), stratified Cox model, and Cochran-Mantel-Haenszel test 
method. In the event that there are small strata (<5), for the purpose of analysis, strata will be 
combined to ensure sufficient number of patients, responses, and events in each stratum. The 
order of stratification factors will be combined in the order of histological subtype, investigator’s 
choice chemotherapy, and PD-L1 status until the count in every stratum is at least 5. 
The monotherapy arms (either nemvaleukin alone or pembrolizumab alone) are included in the 
study for reference only and descriptive estimates of efficacy will be provided for those arms. 
6.2. 
Analysis of the Primary Endpoint 
The primary efficacy endpoint is overall survival (OS). OS is defined as the time from 
randomization to death due to any cause. Patients lost to follow-up before the cut-off date 
without documentation of death will be censored at the last known alive date. 
The date of last contact will be derived for participants not known to have died at the analysis 
cutoff using the latest complete date among the following: 
• Date of randomization 
• Participant assessment dates (e.g. blood draws [laboratory, PK], vital signs, ECOG 
performance status, ECG, tumor assessments, or tumor biopsy dates) 
• Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
• Adverse Event (AE) start and end dates 
• Concomitant medication start and end dates 
• Concomitant radiotherapy start and end dates 
• Date of contact collected on the long-term follow-up eCRF where status is alive 
• Study treatment start and end dates 
• Date of last contact and date of discontinuation on disposition eCRF pages (do not use if 
reason for discontinuation is lost to follow-up). 


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Only dates associated with actual contact/assessment of the participant will be used in the 
derivation. Dates associated with a technical operation unrelated to participant status such as the 
date a blood sample was processed will not be used. Assessment dates after the cutoff date will 
not be applied to derive the last contact date. 
OS will be calculated as duration from date of randomization to the date of death or censoring.  
The statistical hypothesis test, where HR is the hazard ratio, is: 
H0 (Null Hypothesis): HR (combination/chemotherapy) = 1 
Ha (Alternative Hypothesis): HR (combination/chemotherapy) < 1 
The primary estimand for OS is described by the following attributes: 
• Population: patients with platinum-resistant epithelial ovarian, fallopian tube, or primary 
peritoneal cancer 
• Endpoint: OS 
• Treatment condition: nemvaleukin in combination with pembrolizumab versus 
investigator’s choice chemotherapy 
• Intercurrent event: 
o Start of new anti-cancer therapy is addressed with treatment policy strategy 
o Treatment discontinuation is addressed with treatment policy strategy 
• Summary measure: Hazard ratio 
The treatment difference in OS will be assessed by the stratified log-rank test, and p-value will 
be reported. A stratified Cox proportional hazard model will be used for modeling the treatment 
effect between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, respectively). 
The Efron method will be used for handling the ties. The HR and its associated 95% CI from the 
Cox model will be reported. 
OS will be displayed by Kaplan-Meier curves. Median OS and its 95% CI will be provided. The 
CI for median OS will be based on Brookmeyer-Crowley method using log-log transformation 
(Brookmeyer and Crowley 1982). The 1-year and 2-year OS rate will be estimated using the 
Kaplan-Meier method. CIs for the survival function estimates at the time points defined above 
will be derived using the log-log transformation. 
Frequency (number and percentage) of patients with an event (death) and censoring reasons will 
be presented by treatment arm. Censoring reasons are as follows: 
• Alive 
• Withdrawal of consent 
• Lost to follow-up. 
 
Time of Follow-Up for OS 
 
OS follow-up duration is defined as the time from date of randomization to date of death or date 
which patients were censored for overall survival. Median OS follow-up duration will be 
estimated using the reverse Kaplan-Meier method, i.e. Kaplan-Meier estimate reversing the OS 
censoring and event indicators.  


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6.2.1. 
Sensitivity Analyses of the Primary Endpoint 
The following sensitivity analyses are planned for the primary endpoint: 
• OS will be compared between the Combination and the Chemotherapy arms (Arm 1 
and Arm 4, respectively) using the unstratified log-rank test based on the ITT 
Population, and p-value will be reported. The unstratified Cox proportional hazard 
model will be used to assess the treatment effect between the Combination and the 
Chemotherapy arms (Arm 1 and Arm 4, respectively) based on the ITT Population. 
The Efron method will be used for the handling of ties. The hazard ratio (HR) will be 
reported with 95% CI. 
• To account for the potential non-proportional hazards effect associated with 
immunotherapies, OS will be compared between the Combination and the 
Chemotherapy arms (Arm 1 and Arm 4, respectively) using the Fleming and 
Harrington weighted log-rank test with parameter (rho=0, gamma=1) stratified by 
factors used for randomization based on the ITT Population. The p-value will be 
reported. 
• To address the possible violation of the proportional hazard assumption, a restricted 
mean survival time (RMST) with the ITT Population based on the area under the 
curve (AUC) for survival will be implemented using different truncation points 
(every 3 months starting from the median OS on the Combination arm through a 
timepoint where at least 5% of patients remain at risk). The estimated RMST 
difference in OS between the Combination and the Chemotherapy arms (Arm 1 and 
Arm 4, respectively) will be reported with 95% CIs. The SAS procedure such as 
RMSTREG will be used with a linear link function, and the model will adjust for the 
stratification factors. 
• Additional analyses of OS adjusting for the effect of subsequent treatment may be 
performed based on recognized methods [eg, the Rank Preserving Structural Failure 
Time (RPSFT) model (Robins and Tsiatis 1991)], if a sufficient proportion of 
participants receive a subsequent therapy. The choice of the method will be based on 
an examination of the appropriateness of the data to the assumptions required by the 
method. 
6.3. 
Analysis of Secondary Endpoints 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from randomization to the first 
documentation of objective tumor progression per RECIST v1.1 or death due to any cause. 
For patients who have PD while on study treatment, the date of disease progression will be the 
date of the first assessment at which PD is objectively documented per RECIST v1.1 . If the 
patient discontinues study treatment for reasons other than documented PD per RECIST v1.1, 
then the date of disease progression will be the date of the first assessment at which PD is 
objectively documented per RECIST v1. during the Follow-up Period and prior to start of new 
anticancer treatment. Death is considered as a confirmed PD event. In case PD or death are 
observed immediately after 2 or more missed consecutive tumor assessments, PFS will be 


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censored at the date of the last tumor assessment immediately before 2 or more missed 
consecutive tumor assessments. All remaining patients will be censored at the last known date at 
which the patient was considered progression-free. 
PFS will be calculated from the date of randomization to the date of PD or death, whichever 
occurs first.  
The primary estimand for PFS per RECIST v1.1 is described by the following attributes: 
• Population: patients with platinum-resistant epithelial ovarian, fallopian tube, or primary 
peritoneal cancer 
• Endpoint: PFS per RECIST v1.1 
• Treatment condition: nemvaleukin in combination with pembrolizumab versus 
investigator’s choice chemotherapy 
• Intercurrent event: 
o New anti-cancer therapy that started before PD per RECIST v1.1 or death is 
addressed with hypothetical strategy  
o Treatment discontinuation is addressed with treatment policy strategy 
o 2 or more missed consecutive tumor assessments is addressed with hypothetical 
strategy 
• Summary measure:  Hazard ratio 
The main analysis for the primary estimand will be based on investigator assessment. Sensitivity 
analysis will be conducted based on central assessment using similar approach. 
A stratified Cox proportional hazard model will be used for modeling the treatment effect 
between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, respectively). The 
Efron method will be used for handling the ties. The HR and its associated 95% CI will be 
reported. 
The median PFS will be provided along with the 95% CI. The CI for median PFS will be based 
on Brookmeyer-Crowley method using log-log transformation (Brookmeyer and Crowley 1982). 
In addition, Kaplan-Meier curves will be provided. The 6-month, 9-month, or 1-year PFS rate 
will be estimated using the Kaplan-Meier method. CIs for the survival function estimates at the 
time points defined above will be derived using the log-log transformation. 
The censoring rules for PFS are summarized in Table 3. 
Table 3: 
Censoring Rule for Progression-free Survival 
Cases 
Analysis 
No baseline disease assessments and no death 
Censored at the date of randomization 
No post-baseline evaluable disease assessments 
(prior to new anticancer treatment, if initiated) and 
no death 
Censored at the date of randomization 


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Cases 
Analysis 
PD per RECIST v1.1 or death documented after 
≤1 missed tumor assessmenta 
Progressed at the date of documented PD or death, 
whichever occurs first 
With post-baseline evaluable tumor assessments, 
new anticancer treatment is not initiated, and no 
documented PD per RECIST v1.1 or death 
Censored at the date of last evaluable tumor 
assessment 
Patients received a new anticancer treatment that 
started before PD per RECIST v1.1 or death 
Censored at the last evaluable tumor assessment 
where the patient was documented as progression-
free on or prior to the intervention 
PD per RECIST v1.1 or death at the next tumor 
assessment immediately after 2 or more missed 
consecutive tumor assessmentsa 
Censored at the date of the last evaluable tumor 
assessment immediately before 2 or more missed 
consecutive tumor assessments 
Abbreviations: PD=progressive disease; PFS=progression-free survival 
a Refer to Section 13.1 for details regarding missed tumor assessment. 
 
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Censoring reasons are as follows: 
• Ongoing in the study without an event 
• No baseline assessment 
• No adequate post baseline assessments 
• Start of new anticancer therapy 
• Event after 2 or more missing assessments 
• Withdrawal of consent 
• Lost to follow-up. 
PFS2 (Delayed PFS) Analysis 
PFS2 as assessed by the investigator is defined as the time from randomization to subsequent 
disease progression after initiation of new anticancer therapy, or death from any cause, 
whichever occurs first. If progression after next-line therapy cannot be measured, a PFS event is 
defined as end or discontinuation of next-line treatment or death from any cause, whichever 
occurs first. Patients alive and for whom a PFS event has not been observed should be censored 
at the last time known to be alive and without second disease progression. The same statistical 
model for PFS will be used for the PFS2 analysis. 
The following censoring rules will be applied for PFS2:  
Subjects who did not receive subsequent anti-cancer therapy:  
• Subjects who died, the death date is the event date;  
• Else the subject’s PFS2 is censored at his last known alive date.  
Subjects who received subsequent anti-cancer therapy:  
• Subjects who had  disease progression after the start of subsequent anti-cancer therapy, 
this disease progression date is the event date;  


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• Else if a subject died or discontinued subsequent anti-cancer therapy, the \ minimum of 
(date of death, date of discontinuation of subsequent anti-cancer therapy) is the event 
date;  
• Else the subject’s PFS2 is censored at his last known alive date. 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients in the analysis population 
who have a complete response (CR) or partial response (PR) based on RECIST v1.1. 
The best overall response (BOR) is the best response recorded from the date of randomization 
until initial documented disease progression or start of a new anticancer treatment, whichever 
occurs first, taking into account the requirements for confirmation. Confirmation of CR or PR is 
required for assessment of BOR unless otherwise specified. The following rules are considered 
when assigning the confirmed BOR: 
• Complete Response (CR) requires at least two determinations of CR at least 4 weeks 
apart and prior to progression or start of new anticancer therapy. Subsequent 
documentation of a CR may provide confirmation of a previously identified CR even 
with an intervening not evaluable (NE), eg, CR NE CR. 
• Partial Response (PR) requires at least two determinations of PR or better at least 
4 weeks apart (and not qualifying as CR) and prior to progression or start of new 
anticancer therapy. Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or stable disease (SD), eg, PR 
NE PR or PR SD PR. However, only 1 intervening NE or SD will be allowed 
between PRs for confirmation. 
• Stable Disease (SD) or non-CR/non-PD (applicable only to participants without 
measurable disease at baseline) requires at least one SD or non-CR/Non-PD 
assessment (or better) at least once after the first dose and prior to progression or start 
of new anticancer therapy at a minimum duration of 6 weeks – 7 days, ie, 35 days 
(not qualifying as CR or PR).  
• Best overall response of progressive disease (PD) requires progression at or prior to 
the second disease assessment not otherwise qualifying as CR, PR, or SD. Clinical 
deterioration will not be considered as documented disease progression. 
• If the criteria for best overall response of CR, PR, SD, or PD are not met, including 
due to lack of postbaseline assessments, postbaseline assessments of non-evaluable 
(NE), start of new anticancer therapy prior to first postbaseline assessment, SD of 
insufficient duration, or PD after multiple NE assessments, will be consider as NE. 
In case there are any post-treatment responses recorded prior to the initiation of new anticancer 
treatment or progression of disease, whichever occurs first, these responses will be included to 
determine the BOR. The ORR will be based on BOR. 
The primary estimand for ORR per RECIST v1.1 is described by the following attributes: 
• Population: patients with platinum-resistant epithelial ovarian, fallopian tube, or primary 
peritoneal cancer 


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• Endpoint: ORR per RECIST v1.1 
• Treatment condition: nemvaleukin in combination with pembrolizumab versus 
investigator’s choice chemotherapy 
• Intercurrent event: 
o Start of new anti-cancer therapy is addressed with while-on-treatment strategy 
o Death prior to response assessment is addressed with composite strategy 
o Treatment discontinuation is addressed with treatment policy strategy 
• Summary measure:  difference of ORR between nemvaleukin in combination with 
pembrolizumab and investigator’s choice chemotherapy 
The main analysis for the primary estimand will be based on investigator assessment. Sensitivity 
analysis will be conducted based on central assessment using similar approach. 
The analysis of ORR between the Combination and the Chemotherapy arms (Arm 1 and Arm 4, 
respectively) will be conducted by the CochranMantel-Haenszel (CMH) test based on 
randomization stratification factors. The ORR difference and its associated 95% CI will be 
reported. A waterfall plot and swimmer plot based on RECIST v1.1 will be used to display the 
characteristics of the responses in patients. 
In addition to ITT population, ORR will be also summarized in the patients who received the 
study drug and have measurable disease at baseline. 
Duration of Response 
Duration of Response (DOR) is defined as the time from the first documentation of CR or PR to 
the first documentation of objective tumor progression or death due to any cause. Patients who 
never achieve CR or PR prior to starting any new anticancer treatment will be excluded from the 
analysis. DOR is based on a non-randomized subset of patients (specifically, patients who 
achieve an objective response). Therefore, a formal hypothesis testing will not be performed for 
this endpoint. 
DOR will be calculated as follows (in weeks): (date of disease progression/death – date of first 
response (CR or PR) + 1) ÷ 7. 
The distribution of DOR will be estimated using the Kaplan-Meier method. Kaplan-Meier 
estimates for the median DOR will be provided along with two-sided 95% CI. The CI for median 
will be based on the Brookmeyer-Crowley method using log-log transformation (Brookmeyer 
and Crowley 1982). Kaplan-Meier curves will also be provided. 
The censoring rule for DOR is the same as that of PFS. 
Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of patients with objective evidence of 
CR, PR, or stable disease (SD). For SD, measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 6 weeks – 7 days of visit window, ie, 35 days. 


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The DCR will be analyzed using the CMH test based on randomization stratification factors. The 
difference and its associated two-sided 95% CI will be reported.Time to Response 
Time to response (TTR) is defined as the time from randomization to the first documentation of 
CR or PR. Patients who never achieve CR or PR prior to starting any new anticancer treatment 
will be excluded from the analysis. No censoring observation will occur by definition. Time to 
response is based on a non-randomized subset of patients (specifically, patients who achieve an 
objective response); therefore, formal hypothesis testing will not be performed for this endpoint. 
Comparisons between treatment arms will be made for descriptive purposes. 
The TTR will be calculated as follows (in weeks): (date of first response [Complete or Partial] – 
date of randomization + 1) ÷ 7. 
Cancer Antigen-125 Response 
A CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline, and 
the response must be confirmed and maintained for at least 28 days as per the GCIG. The 
number of responders will be analyzed using the CMH test based on randomization stratification 
factors. The response difference and its associated two-sided 95% CI will be reported. 
In addition, the change from baseline value in CA-125 will be summarized with descriptive 
statistics. 
6.4. 
Analysis for Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include the PFS, ORR, DOR, TTR, as assessed by 
Investigator based on RECIST v1.1 and OS for the monotherapy arms. The analysis of these 
endpoints will be summarized in the same manner as the secondary efficacy endpoints are 
analyzed, as noted in Section 6.3. 
7. 
SAFETY ANALYSIS 
7.1. 
 General Considerations 
All safety endpoints will be summarized for the Safety Population. 
In general, all by-visit summaries of safety parameters will only include baseline, Day 1 of first 
6 cycles, and the EOT visit. Additional summaries will be derived as the minimum and 
maximum for all on-study assessments and presented similarly at the end of the summary table. 
Unscheduled measurements will not be used in computing the descriptive statistics for change 
from baseline at each post-baseline time point. However, the maximum and minimum 
calculations will use all post-baseline data, including any unscheduled assessments. 
7.2. 
Adverse Events 
Adverse events will be coded using the most recent version of MedDRA. Treatment-emergent 
AEs (TEAEs) are defined as AEs that that have an onset on or after the day of the first dose of 
study drug  until 30 days after the last dose of study drug (90 days for serious adverse events 
[SAEs]). or until the start of new anti-cancer therapy, whichever is earlier. A single post-


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treatment time window will be used for SAE in the TEAE definition for consistency across 
treatment arms.   
Events where the onset date was the same as the study drug start date will be assumed to be 
treatment-emergent, unless the study drug start time and the AE start time are collected, and the 
AE start time is prior to the study drug start time. If an incomplete onset date is collected for an 
AE, the AE will be assumed to be treatment-emergent unless there is evidence that confirms that 
the AE was not treatment-emergent (eg, the AE end date is prior to the date of the first dose of 
study drug). 
TEAEs will be summarized by preferred term (PT) and by system organ class (SOC) when 
applicable. Patients reporting more than one AE within a SOC will be counted only once for that 
SOC. Patients reporting the same AE more than once will be counted only once for that PT. 
The severity of TEAEs will be assessed by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE). For TEAEs that are not specified in the NCI 
CTCAE, severity grade is assigned by the criteria in the protocol. If a patient has the same AE on 
multiple occasions, the highest severity recorded for the event will be presented in the AEs-by-
severity table. 
An overview table, including the number and percentage of patients with TEAEs, serious 
TEAEs, serious treatment-related TEAEs, TEAEs related to study drug, grade 3 to 4 TEAEs, 
grade 3 to 4 treatment-related TEAEs, TEAEs leading to treatment discontinuation, TEAEs 
leading to dose reduction, TEAEs leading to dose interruption, and TEAEs leading to death, will 
be summarized. 
In addition, the number and percentage of subjects experiencing TEAEs will be summarized by 
treatment arm for the following: 
• TEAEs by SOC and PT 
• TEAEs by PT 
• Treatment-related TEAEs by SOC and PT (Related to Any Study Treatment)    
• Treatment-related TEAEs by PT (Related to Any Study Treatment, and related to each 
drug component for combination therapy)  
• TEAEs by maximum CTCAE toxicity grade and PT    
• Treatment-related TEAEs by maximum CTCAE toxicity grade and PT (Related to Any 
Study Treatment, and related to each drug component for combination therapy)    
• Serious TEAEs by SOC and PT 
• Serious TEAEs by PT 
• Treatment-related Serious TEAEs by PT (Related to Any Study Treatment, and related to 
each drug component for combination therapy) 


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• TEAEs leading to discontinuation by PT (of Any Study Treatment, and of each drug 
component for combination therapy) 
• TEAEs leading to dose interruption by PT (of each drug component as applicable) 
• TEAEs leading to dose reduction by PT (of each drug component as applicable) 
• TEAEs leading to death by PT 
Listings will be provided for all AEs, serious TEAEs, AESIs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose reduction, TEAEs leading to dose interruption, and 
TEAEs leading to death. Adverse events observed beyond 30 days (90 days for SAE) after the 
last dose of study drug will be listed. The AE onset date and duration will be shown on all 
listings of AEs. 
The following Preferred Terms will be grouped in order to describe a medical condition rather 
than a single event: neutropenia (neutropenia/ neutrophil count decrease), anemia (anemia/ 
haemoglobin decrease), thrombocytopenia (thrombocytopenia/ platelet count decrease), 
lymphopenia (lymphopenia/ lymphocyte count decrease), and supraventricular extrasystoles 
(supraventricular extrasystoles/ supraventricular tachycardia). 
Summaries of characteristics for neutropenia will be provided. 
7.2.1. 
Adverse Events of Special Interest  
Adverse events of special interest (AESIs) are known or potential risks following nemvaleukin 
administration for which additional guidance is provided. These include infusion-related reaction 
(IRR)/Cytokine Release Syndrome (CRS), Capillary Leak Syndrome (CLS), and Immune-related 
Adverse Events (irAEs).  
The number and percentage of patients experiencing at least one TEAE for AESIs as reported by 
the investigator per the AESI eCRF will be summarized for each AESI category as follows: 
• Overview of AESI, along with characteristics for each AESI category 
• AESIs by AESI category and PT 
• AESIs by AESI category, maximum CTCAE toxicity grade and PT 
7.2.2. 
Death 
The death reasons will be collected in the electronic case report form (eCRF) and will include: 1) 
Progressive Disease, 2) Adverse Event, 3) Other, or 4) Unknown.  
The number and percentage of patients for each death reason will be summarized for all 
participants and participants who died during treatment period respectively. 
Listings will be provided for patients who died during the study for any reason, and for patients 
who died due to an AE. 
 


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7.3. 
Clinical Laboratory Parameters 
Blood and urine samples for clinical laboratory assessments will be collected at pre-specified 
timepoints. Specific hematology, biochemistry, urinalysis, and coagulation assessments are listed 
in Table 4. 


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Table 4: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Coagulation 
• Hematocrit 
• Hemoglobin 
• Red blood cell count 
• Total and differential 
(absolute) white blood cell 
count 
• Absolute counts for 
neutrophils, lymphocytes, 
monocytes, and 
eosinophils 
• Platelet count 
• C-reactive protein 
General Chemistry 
• Albumin 
• Bicarbonate 
• Calcium 
• Chloride 
• Creatine phosphokinase 
(CPK) 
• Glucose 
• Magnesium 
• Phosphorus 
• Potassium 
• Sodium 
• Total protein 
• Uric acid 
• Amylase 
• Lipase 
Renal Function Tests 
• Blood urea nitrogen 
(BUN) 
• Creatinine 
Liver Function Tests 
• Alanine transferase (ALT) 
• Alkaline phosphatase 
(ALK-P) 
• Aspartate 
aminotransferase (AST) 
• Lactic dehydrogenase 
(LDH) 
• Total bilirubin 
Endocrine Testsa 
• Thyroid-stimulating 
hormone (TSH)b 
• Adrenocorticotropic 
hormone (ACTH) 
• Total cortisol 
• Free thyroxine (T4) 
• Triiodothyronine (T3) 
• Color and appearance 
• pH 
• Specific gravity 
• Ketones 
• Protein 
• Glucose 
• Bilirubin 
• Nitrite 
• Urobilinogen 
• Leukocytes 
• Occult blood 
• Microscopic examination 
of sediment, only if 
urinalysis dipstick results 
for blood, leukocytes or 
protein are abnormal (ie, 
2+ or higher) 
• International normalized 
ratio (INR) 
• Activated partial 
thromboplastin time 
(aPTT) 
a Endocrine tests will be performed for all patients at Screening. On-treatment endocrine tests are only applicable to Arm 1, 2, and 3. 
b 
If TSH result is abnormal, collect total T3 or free T3 and Free T4. 


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Laboratory parameters will be presented in international standard units. Scheduled laboratory 
parameters assessed by central laboratory will be included in the laboratory results summaries by 
visit timepoints, unless specified otherwise. Unscheduled assessments as well as assessments by 
local laboratories will be included in worst case post baseline assessments.  
Results of clinical laboratory tests will be summarized at pre-specified visits (baseline, Day 1 of 
first 6 cycles, EOT visit, as well as worst case post-baseline) by treatment arm for the actual 
values and for change from baseline. 
In addition, hematology and chemistry laboratory determinations will be categorized according 
to NCI CTCAE grades and shifts from baseline NCI CTCAE grades to maximum and final post-
baseline grades will be summarized for tests that are gradable by CTCAE. The baseline and final 
grades will be defined respectively as the grade of the last measurement collected prior to the 
first dose of study drug, and as the last post-baseline measurement collected no more than 
30 days after the last dose of study drug. The maximum NCI CTCAE toxicity grade value will be 
the value with the highest NCI CTCAE toxicity grade collected after the first dose of study drug 
and within 30 days  after the last dose of study drug. In cases where multiple values are collected 
on the same day, the maximum grade value will be selected as the value for that day. 
For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labelled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia separately. If a lab parameter is graded in both directions (e.g. glucose: 
hyperglycemia and hypoglycemia), then low direction toxicity grades at baseline and post 
baseline will be set to 0 when the variables are derived for summarizing high direction toxicity, 
and vice versa. 
Additional laboratory results that are not part of NCI CTCAE will be presented according to the 
categories: Low (below normal limit), Normal (within normal limits) and High (above normal 
limit) according to the laboratory normal ranges. Furthermore, only the numeric part in 
laboratory values that contain non-numeric qualifiers, such as less than (<) a certain value, or 
greater than (>) a certain value, will be used in the summary statistics.  
Detailed listings of data for patients experiencing NCI CTCAE grade ≥3 hematology and 
chemistry values will be provided. All measurements collected after the first dose of study drug 
and within 30 days after the last dose of study drug will be included in these listings. 
Number of patients who meet the following criterion will be summarized: 
• ALT > 3× upper limit of normal (ULN), ALT > 5× ULN, ALT > 10× ULN, ALT > 20× 
ULN 
• AST > 3× ULN, AST > 5× ULN, AST > 10× ULN, AST > 20× ULN 
• (ALT or AST) > 3× ULN, (ALT or AST) > 5× ULN, (ALT or AST) > 10× ULN, (ALT 
or AST) > 20× ULN 
• Total Bilirubin (TBILI) > 1.5× ULN, TBILI > 2× ULN 
• ALP > 1.5× ULN 
• Concurrent ALT > 3× ULN and TBILI > 1.5× ULN 
• Concurrent AST > 3× ULN and TBILI > 1.5× ULN 
• Concurrent (ALT or AST) > 3× ULN and TBILI > 1.5× ULN 
• Concurrent ALT > 3× ULN and TBILI > 2× ULN 
• Concurrent AST > 3× ULN and TBILI > 2× ULN 


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• Concurrent (ALT or AST) > 3× ULN and TBILI > 2× ULN 
• Concurrent (ALT or AST) > 3× ULN and TBILI > 2× ULN and ALP > 2× ULN 
• Potential Hy’s law: Concurrent (ALT or AST) > 3× ULN and TBILI ≥ 2× ULN and 
ALP ≤ 2× ULN 
Concurrent measurements are those occurring within 3-day window. 
 
A scatter plot of maximum total bilirubin versus maximum ALT/AST will be provided. A listing 
will be provided for patients who meet potential Hy’s law.  
A listing will be provided for patients who experienced pregnancy during the study. 
 
7.4. 
Vital Signs and ECG 
Vital signs (eg, blood pressure, pulse, respiratory rate, and body temperature), height, and weight 
as applicable will be assessed at pre-specified timepoint(s). 
A 12-lead ECG will be conducted at pre-specified timepoint(s). 
7.4.1. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline values after the first dose of study 
drug will be presented at pre-specified timepoints (baseline, Day 1 of first 6 cycles, EOT visit, as 
well as post-baseline minimum and maximum) by treatment arm.  
Patients who meet the potentially clinically significant (PCS) criteria in vital signs will be 
summarized by treatment arm. The PCS is defined as SBP ≥160 or DBP ≥100, or SBP ≤90 or 
DBP ≤60, or Temperature >40℃. 
7.4.2. 
Electrocardiograms 
Frequency (number and percentage) of patients with post-baseline ECGs that are deemed 
clinically significant by the Investigator will be summarized. In addition, a detailed data listing 
for patients with ECG of PCS will be provided. 
7.5. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG Performance Status assesses the patients’ activity status. Descriptions of activity 
status are presented in Table 5. Possible scores are 0 to 5. The number and percentage of patients 
with baseline score versus post-baseline scores will be summarized by treatment arms in a shift 
table. 
Table 5: 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0  
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work).  


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Grade 
Description 
2  
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.  
3  
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.  
4  
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.  
5  
Dead  
7.6. 
Left Ventricular Ejection Fraction 
Left ventricular ejection fraction will be performed only when pegylated liposomal doxorubicin 
was selected as physician’s choice of chemotherapy. For subjects received pegylated liposomal 
doxorubicin, descriptive statistics for left ventricular ejection fraction and changes from baseline 
values will be presented. Frequency (number and percentage) of participants meeting clinically 
significant criteria (shift from normal at baseline to >=20%, >=15% decrease from baseline) will 
be summarized. 
8. 
OTHER EXPLORATORY ANALYSES 
8.1. 
Health-Related Quality of Life Analyses 
The functional assessment of cancer therapy-ovarian (FACT-O) is a 39-item validated 
questionnaire about the past 7 days using a 5-point Likert-type scale (Basen-Engquist et al, 
2001). It includes 5 subscale domains. 
The first 4 domains include a set of general items that assess physical well-being (PWB), 
social/family well-being (SWB), emotional well-being (EWB), and functional well-being 
(FWB); these items are not specific to one type of cancer. The fifth module is comprised of 
12 items that are specific to women with ovarian cancer. In addition to scores from these 
5 domains, three other summary scores will be calculated: 1) the FACT-O Trial Outcome Index 
(TOI) calculated as the sum of the ovarian subscale scores, the PWB, and FWB scores; 2) the 
FACT/National Comprehensive Cancer Network (NCCN) Ovarian Symptom Index (FOSI), a 
validated score based on 8 items selected from the FACT-O; 3) the FACT-O total score, 
calculated as the sum of all 39 items. All FACT-O scores will be calculated according to the 
guidelines from the instrument developers, which can be found at 
https://www.facit.org/measures/FACT-O. The FACT-O will be administered to all study patients 
on Day 1 of every cycle through Year 1, every 12 weeks thereafter, EOT visit and the 30-Day 
Safety Follow-up visit. In addition, patients randomized to Arms 1 and 3 will complete the 
FACT-O on Day 5 of cycles 1 and 2. 
The EQ-5D-5L is a validated quality of life questionnaire developed by the EuroQol Group in 
order to provide a simple, generic utility measure for characterizing current health states of 
patients. The EQ-5D-5L is designed for self-completion by patients. It consists of 2 parts – the 
EQ-5D-5L descriptive system and the Visual Analogue Scale (VAS). 


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The EQ-5D-5L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels. 
The 5-dimensional, 5-level systems are converted into an index value. Values for theoretically 
possible health states are calculated using a regression model and weighted according to the 
social preferences of the US population (Van Hout et al, 2012). 
The VAS records the respondent’s self-rated health on a vertical VAS. The VAS ‘thermometer’ 
has 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the 
bottom. This information can be used as a quantitative health state measure as judged by the 
individual respondents. During the long-term follow up period, only the VAS will be 
administered to patients in all treatment arms. 
The HRQoL endpoints will be analyzed based on the ITT Population who have a baseline and at 
least one post-baseline assessment (for FACT-O and EQ-5D-5L separately). Compliance rate 
will be determined by the number of evaluable forms divided by the number of expected forms. 
Evaluable forms are those where ≥50% of questions for each domain were answered. 
Based on pre-defined within-person meaningful change, the proportion of patients with a best 
response of ‘improved’, ‘no change’ and ‘worsened’ will be calculated for FACT-O TOI, FOSI 
and FACT-O Total. Best response will be derived based on evaluable HRQoL data collected 
from randomization up to the earliest of progression or death. Criteria for determining best 
HRQoL response are shown below. 
Table 6: 
Criteria for Best Overall HRQoL Response  
Category 
Criteria 
Improved 
Two visit responses of “improved” a minimum of 21 days apart without an 
intervening visit response of “worsened”. 
No Change 
Does not qualify for overall score response of “improved”. Two visit responses of 
either “no change” or “improved” and “no change” a minimum of 21 days apart 
without an intervening visit response of “worsened”. 
Worsened 
Does not qualify for overall score response of “improved”. A visit response of 
“worsened” without a subsequent response of “improved” or “no change” within 
21 days. 
Other 
Does not qualify for one of the above. 
Table 7: 
Pre-Defined Thresholds for Meaningful HRQoL Change  
Scale 
Category 
Improved 
No Change 
Worsened 
TOI 
≤ −7 
> −7 and <7 
≥7 
FOSI 
≤ −3 
> −3 and <3 
≥3 
FACT-O Total 
≤ −9 
> −9 and <9 
≥9 
The absolute values and changes from baseline at each administration timepoint in total score 
and subscale domain scores for the FACT-O and EQ-5D-5L index and VAS scores will be 


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descriptively summarized. The number and percentage of patients in the best response will be 
descriptively summarized. 
The change from baseline in scores from FACT-O scores (TOI, FOSI, and FACT-O total), and 
EQ-5D-5L index value and VAS will be analyzed using a mixed model with repeated 
measurements with an unstructured variance-covariance matrix based on the observed data. The 
model will include stratification factors, treatment arm, and interaction term of visit and 
treatment as categorical variables, and baseline score as a covariate. The Kenward-Roger 
approximation will be used to adjust the denominator degree of freedom. The change from 
baseline in the average of all post-baseline visits in the combination arm will be compared to that 
of the chemotherapy group. 
Additional analysis for HRQoL endpoints will be specified in a separate Health Economics and 
Outcomes Research SAP. 
8.2. 
Pharmacokinetic/ Pharmacodynamic Analyses 
The PK and pharmacodynamic analyses will be conducted separately by treatment arms on the 
PK/pharmacodynamic population as appropriate. 
8.2.1. 
Pharmacokinetic Analyses 
Serum samples for evaluation of nemvaleukin PK and/or pembrolizumab PK will be obtained 
from each patient at pre-specified timepoints. 
Concentration data will be summarized descriptively by treatment arm as appropriate according 
to nominal (protocol specified) sampling times. PK concentration data from this study may be 
used in a subsequent population PK analysis or other post hoc analyses conducted outside of this 
study. 
8.2.2. 
Blood Pharmacodynamic Analyses 
The pharmacodynamic effect of nemvaleukin will be assessed by measuring circulating 
CD8+ T cells, Tregs, and NK cells in peripheral blood from each patient at pre-specified 
timepoints. Expression of interleukin (IL)-2 receptors on immune cells and T cell receptor 
clonality may also be assessed. 
In addition, serum samples will be obtained from each patient at pre-specified timepoints. 
Concentration of multiple pro-inflammatory cytokines including interferon-γ, tumor necrosis 
factor-α, IL-1β, IL-6, IL-10, and other soluble proteins will be determined. 
Circulating tumor DNA may be isolated from plasma collected at pre-specified timepoints and 
may be subject to genetic and epigenetic analyses. 
Pharmacodynamic data will be summarized descriptively, including absolute cell counts or 
proportion and concentrations at nominal (protocol-specified) timepoints, as well as fold change 
from baseline for circulating leukocytes (including T and NK cells) and cytokines (including 
interferon-γ and IL-6). Additional analyses may be conducted as deemed necessary upon 
exploration of data. 


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8.2.3. 
Tumor Tissue Pharmacodynamic Analyses 
Tumor biopsy samples from patients will be processed and may be analyzed by 
immunohistochemistry and/or immunofluorescence for tumor infiltrating immune cells. The 
baseline (pre-treatment) values, post-treatment values, and the changes from baseline in density 
of immune cells in tumor tissues may be summarized descriptively in tables. 
Relevant markers for disease (eg, breast cancer gene status and homologous recombination 
repair pathway deficiency status, tumor mutational burden scores, and PD-L1 expression) may 
be summarized descriptively. Additional analyses may be conducted as deemed necessary upon 
exploration of data. 
8.3. 
Immunogenicity Analyses 
Immunogenicity endpoints include the following: 
1. Presence of anti-drug antibodies (ADAs) 
2. Titer of ADAs 
3. Frequency of the presence of anti-drug antibodies by relevant treatment arms 
Time of onset of immunogenicity and time of resolution of immunogenicity will be calculated 
and summarized. Time of onset is defined as the first timepoint with a positive result for ADA; 
time of resolution is defined as the first timepoint when the previously observed positive for 
ADA returns to negative for ADA. Duration of positive immunogenicity response (ADA 
duration) is calculated as the difference between time of resolution of immunogenicity and time 
of onset of immunogenicity. 
Summaries of baseline ADA status (positive or negative) along with number and percentage of 
participants who have treatment emergent ADA will be provided. Treatment emergent is defined 
as either (1) negative at baseline and positive post baseline or (2) positive at baseline and positive 
post baseline where the titer levels demonstrate a 4-fold increase post baseline. 
Positive samples titer values will be categorized as appropriate (eg. <100, ≥100 to <1000, >1000) 
and summarized. 
Additional immunogenicity characterization (eg, presence of neutralizing anti-drug antibodies) 
will be summarized. 
9. 
INTERIM ANALYSES 
The Sponsor’s study team members will be blinded to any aggregate summaries of efficacy data 
by assigned treatment group during the study conduct. The interim analyses planned in this study 
are described below. All of the analyses will be conducted by an independent statistician under 
the guidance of an independent data monitoring committee (IDMC).  More details can be found 
in the IDMC charter. Upon review of the IA by the IDMC and sponsor senior management, the 
study team may be unblinded after the IA to facilitate regulatory submission. 


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9.1. 
Interim Futility Analysis of ORR in Each Monotherapy Arm 
The monotherapy arms (either nemvaleukin alone or pembrolizumab alone) are included in the 
study as reference arms to isolate the component effect; thus, no statistical comparison or testing 
will be conducted against or between the monotherapy arms. 
Interim analyses will be conducted separately when the 24th patient enrolls into the nemvaleukin 
monotherapy arm and the 12th patient enrolls into the pembrolizumab monotherapy arm; these 
analyses will be conducted by an independent statistician. The interim analysis on the ORR will 
provide a statistical recommendation for early stopping for futility. 
The stopping boundary is summarized in Table 8. 
Table 8: 
Stopping Boundary for Interim Futility Analysis of ORR in Monotherapy 
Arms 
Monotherapy Arm: 
Interim analysis at:  
Recommend stopping enrollment if:  
Pembrolizumab 
Monotherapy Arm 
First 12 dosed patients 
0 or 1 response (confirmed PR or CR) 
Nemvaleukin 
Monotherapy Arm 
First 24 dosed patients  
0 response (confirmed or unconfirmed PR or 
CR or durable SD lasting for ≥3 months)  
Abbreviations: CR=complete response; PR=partial response; SD=stable disease. 
If the futility criteria are met, further enrollment into the arm will stop; patients in the arm 
receiving benefit (SD or better) may remain on study until progression. Crossover to another 
treatment arm is not allowed. (Note: all patients at any time who progress will be immediately 
discontinued from treatment.) 
There will be no type I error rate adjustment caused by this futility analysis, as the monotherapy 
arms are not included for any statistical comparisons. 
9.2. 
Interim Efficacy Analysis of OS 
One interim analysis (IA)  of OS are planned in the study. The statistical comparison will be 
performed between the Combination and the Chemotherapy arms. 
The study is event-driven. The planned OS IA will be performed when approximately 215 events 
(at approximately 75% information fraction) are observed in the two arms (the Combination and 
the Chemotherapy arms). The final analysis of OS  will be performed when approximately 286 
deaths will have been observed in the two arms (the Combination and the Chemotherapy arms). 
The Lan-DeMets O’Brien-Fleming alpha spending function is constructed to implement group 
sequential boundaries to control the overall type I error rate at 2.5% (one-sided) for OS. 
Table 9 summarizes the analysis strategies. If the actual number of OS events at the IA and FA 
differs from those specified in the table, the boundaries will be adjusted using the Lan-DeMets 
O’Brien-Fleming spending function accordingly. 


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Table 9: 
Summary of Number of Events and Decision Guidance at the Planned OS 
Analyses  
Analysis 
Expected Number of Events at the Time of Analysis 
Efficacy Boundary 
p-valuea 
HR 
OS IA 
~215 OS events in the Combination and the 
Chemotherapy arms 
0.0096 
0.7265 
OS FA 
~286 OS events in the Combination and the 
Chemotherapy arms 
0.0221 
0.7882 
Abbreviations: FA=final analysis; HR=hazard ratio; IA=interim analysis 
a p-value (1-sided) is the nominal significance level for testing and will be used to claim crossing of a boundary. 
9.3. 
Blinding and Independent Data Monitoring Committee 
An IDMC will be established by the Sponsor to analyze and interpret the data for the interim 
analysis. Members will include experts in oncology and biostatistics who are not participating in 
this study in any capacity and do not have any external conflict of interest for the study. The 
IDMC members and specific duties will be fully described in an IDMC charter. 
The Sponsor’s study team members will remain blinded to any aggregate summaries of efficacy 
data by assigned treatment group during the study conduct until the primary efficacy analysis 
timepoint.  Upon review of the IA by the IDMC and sponsor senior management, the study team 
may be unblinded after the IA to facilitate regulatory submission. 
10. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
There are no changes in conduct or planned analyses from the protocol. 
11. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
11.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits at scheduled timepoints as specified in the protocol. 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in the eCRF. There will be one valid value of assessment kept for each scheduled analysis visit in 
summary/analysis statistics. 
Unscheduled visits are visits with data collected outside of scheduled time points. Unscheduled 
visits will not be used for by-visit summary/analysis statistics, unless specified otherwise. 
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:  
Study day = Date of the assessment/event - start of study treatment + 1. 
 


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The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as: 
Study day = Date of the assessment/event - start of study treatment. 
11.2. 
Safety Data Handling 
All efforts should be made to obtain missing information from the Investigator. For vital signs, 
laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only observed data 
will be used for analyses, and missing data will not be imputed. 
Adverse events with missing severity are classified as “severe”; AEs with missing relationship to 
study drug are classified as “related”. 
Missing start dates of AEs will be imputed following the algorithms below: 
• If the day, month, and year are all missing: 
− Use the date of the first study drug administration. 
• If the day and month are missing: 
− Use the date of the first study drug administration if the year is the same as the 
year of the first study drug administration. 
− Use the day and month of 31 December if the year is prior to the year of the first 
study drug administration. 
− Use the day and month of 01 January if the year is after the year of the first study 
drug administration. 
• If the day is missing: 
− Use the date of the first study drug administration if the month and year are the 
same as those of the first study drug administration. 
− Use the last day of the month if the month is prior to and the year is the same as 
those of the first study drug administration. 
− Use the first day of the month if the month is after and the year is the same as 
those of the first study drug administration. 
− For any other cases, use the first day of the month. 
11.3. 
Handling of Partial Dates of Concomitant Medication 
The algorithm for determining prior and concomitant medications is described below. 
A conservative principle will be applied; that is, if there is any missing or partially missing 
medication start and/or stop date, and it cannot be determined definitively whether a medication 
was taken concomitantly with study drug, it will be assumed that the medication is concomitant. 
If a medication stop date is partially known, the medication stop date will be imputed as latest 
possible date (ie, last day of month if day is unknown), or 31 December if both the day and 
month are unknown. If a medication start date is partially known, the medication start date will 


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be imputed as the earliest possible date (ie, first day of month if day is unknown), or 01 January 
if both day and month are unknown. 
11.4. 
Reporting Precision 
Summary statistics will be presented to the degree of precision listed in Table 10, unless 
otherwise specified. 
Table 10: 
Degree of Precision 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places 
Minimum, Maximum 
The same as the raw data, up to 2 decimal places 
p-value 
Rounded to 3 decimal places and therefore presented as 
0.xxx; p-values smaller than 0.001 as ‘<0.001’; p-values 
greater than 0.999 as ‘>0.999’. 
Percentage 
One decimal place. A percentage of 100% will be reported as 
100%. Percentages of zero will be reported as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12–0.30). 
For weight, height, and BMI, one decimal place will be used for summary statistics. 
12. 
REFERENCES 
Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA, et al. Reliability and validity of the 
functional assessment of cancer therapy-ovarian. J Clin Oncol. 2001;19(6):1809-1817. doi: 
10.1200/JCO.2001.19.6.1809. 
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. Biometrics. 
1982;38(1):29-41. doi: 10.2307/2530286. 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics - Theory and Methods. 
1991;20(8):2609-2631. doi: 10.1080/03610929108830654. 
van Hout B, Janssen MF, Feng Y-S, et al. Interim Scoring for the EQ-5D-5L: Mapping the EQ-
5D-5L to EQ-5D-3L Value Sets. Value Health. 2012;15(Jul-Aug):708-715. doi: 
10.1016/j.jval.2012.02.008. 
 


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13. 
APPENDIX 
13.1. 
Extended Time Without an Evaluable Tumor Assessment 
Given the scheduled tumor assessment, ie, q6w (±7 days) during the first year of study 
participation and q12w (±7 days) thereafter, the following rules will be used to calculate the 
missed tumor assessment for PFS to identify extended time without an evaluable tumor 
assessment. 
If the duration between the event (PD/death) and last evaluable tumor assessment prior to the 
new anticancer treatment is more than the window, PFS will be censored at the last evaluable 
tumor assessment prior to the event (PD/death) and the new anticancer treatment; the date of 
randomization will be used if there are no post-baseline evaluable assessments. 
Define Event Day (since randomization) and Duration (without an evaluable tumor assessment) 
as below: 
• Event Day = min(PD/Death date) − randomization date + 1 
• Duration = min(PD/Death date) − last evaluable assessment date + 1 if with post-
baseline evaluable assessments 
Table 11 presents the situations of PD or death documented ≥2 missed tumor assessments; 
otherwise, it will be considered as PD or death documented ≤1 missed tumor assessments. 
Table 11: 
Determination of ≥2 Missed Tumor Assessments 
Scenario 
Considered as ≥2 Missed Tumor Assessments 
With last evaluable tumor 
assessment 
91 days < Event Day ≤385 days, and Duration >98 days  
385 days < Event Day <539 days, and Duration >140 days 
Event Day ≥ 539 days, and Duration >182 days 
No baseline or no post-baseline 
evaluable tumor assessment 
Event Day >91 days