Conditions: Advanced Solid Tumors
Keywords: Immunotherapy IL-2 Interleukin-2 Solid tumors Melanoma Renal cell carcinoma Non-small-cell lung cancer Squamous cell carcinoma of the head and neck in combination with pembrolizumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 243
Healthy volunteers: no

Brief summary:
To better understand the safety and tolerability of ALKS 4230 in humans

Detailed description:
To investigate the safety and tolerability of ALKS 4230, determine the recommended Phase 2 dose (RP2D) and assess anti-tumor activity in Monotherapy and ALKS 4230 in Combination with pembrolizumab.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: ALKS 4230 intervention 2: ALKS 4230 + pembrolizumab
Intervention descriptions: intervention 1: Intravenous (IV) infusion over 30 minutes given daily for 5 consecutive days followed by an off-treatment period intervention 2: IV infusion of ALKS 4230 over 30 minutes given daily for 5 consecutive days followed by an off-treatment period; pembrolizumab administered IV once with ALKS 4230 on the first day of each cycle

Protocol document:
Prot_000.pdf: 
1. 
TITLE PAGE 
 
CLINICAL STUDY PROTOCOL 
ALK4230-A101 
 
Study Title 
A Phase 1/2 Study of ALKS 4230 Administered Intravenously as 
Monotherapy and in Combination With Pembrolizumab in Subjects 
With Advanced Solid Tumors - ARTISTRY-1 
EudraCT Number 
2019-001998-90 
Version / Date 
Version 13.0: 08 Sep 2022 
Version 12.0: 10 Feb 2020 
Version 11.0: 01 May 2019 
Version 10.0: 09 Aug 2018 
Version 9.0: 22 May 2018 
Version 8.0: 12 Jan 2018 
Version 7.0: 20 Dec 2017 
Version 6.0: 06 Oct 2017 
Version 5.0: 08 Jun 2017 
Version 4.0: 11 Oct 2016 
Version 3.0: 10 Feb 2016 
Version 2.0: 13 Oct 2015 
Original Protocol: 07 Jul 2015 
Sponsor 
Alkermes, Inc. 
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 Alkermes, Inc. No person is authorized to make it public without the written 
permission of Alkermes, 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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2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of Investigational Product: ALKS 4230  
Name of Active Ingredient: Not applicable. 
Title of Study: A Phase 1/2 Study of ALKS 4230 Administered Intravenously as Monotherapy and in 
Combination With Pembrolizumab in Subjects With Advanced Solid Tumors - ARTISTRY-1 
Investigators/Study Sites: The study will be conducted in globally with up to 36 sites. 
Study Period: 
Date of first subject’s consent: September 2016 
Estimated duration of study (excluding the Extension Phase): 
5 years 
Phase of Development: 1/2 
Primary Objectives: 
• 
To investigate the safety and tolerability of ALKS 4230 and to determine the maximum 
tolerated dose and the recommended Phase 2 dose (RP2D) of ALKS 4230 in subjects with 
advanced solid tumors who are refractory or intolerant to therapies known to provide 
clinical benefit (Part A) 
• 
To assess the safety profile and characterize antitumor activity by overall response rate 
(ORR) of ALKS 4230 at the RP2D in subjects with melanoma or renal cell carcinoma 
(RCC) (Part B) 
• 
To characterize the safety profile and antitumor activity by ORR of ALKS 4230 
administered intravenously (IV) in combination with pembrolizumab in subjects with 
advanced solid tumors (Part C) 
• 
To describe the dose-limiting toxicity (DLT) of ALKS 4230 (Part A) 
Secondary Objectives: 
• 
To characterize the clinical pharmacokinetic (PK) profile and immunogenicity of 
ALKS 4230 alone (Part A and Part B) and in combination with pembrolizumab (Part C) 
• 
To investigate the clinical pharmacodynamic effects of ALKS 4230 alone (Part A and Part 
B) and in combination with pembrolizumab (Part C) 
• 
To describe any antitumor activity and responses observed with ALKS 4230 (Part A) 
• 
To evaluate the duration of response (DOR), durable response rate (DRR), and time to 
response for subjects treated with ALKS 4230 in each of the expansion cohorts (Part B) 
and in combination with pembrolizumab (Part C) 
Exploratory Objectives: 
• 
To describe changes in post-treatment subject blood and/or tumor tissue samples as 
compared with baseline/pretreatment samples (Part B) 
• 
 
 
 


 
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• 
 
 
 
Primary Endpoints: 
• 
The incidence of DLTs from the first dose through the end of the DLT observation period 
(Part A) 
• 
The incidence and severity of treatment-emergent AEs according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or 
higher (Parts A, B, and C) 
• 
ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
version 1.1 (Eisenhauer et al 2009) (Part B and Part C) 
Secondary Endpoints: 
• 
Serum concentrations of ALKS 4230 and descriptive PK parameters  
• 
Presence of anti-ALKS 4230 antibodies in serum 
• 
Immune (i-) ORR (iORR) based on Immune RECIST (iRECIST) guidelines (Seymour et al 
2017) 
• 
Disease control rate (DCR) based on RECIST guidelines and immune DCR (iDCR) based 
on iRECIST guidelines 
• 
DOR based on RECIST guidelines and immune DOR (iDOR) based on iRECIST 
guidelines 
• 
DRR based on RECIST and immune DRR (iDRR) based on iRECIST guidelines for Part B 
and Part C Cohorts C5, C6, C7 only 
• 
Progression-free Survival (PFS) and immune PFS (iPFS) for Part B and Part C Cohorts C5, 
C6, C7 only 
• 
Numbers of circulating CD8+ T cells, regulatory T cells (Tregs), and natural killer (NK) 
cells in peripheral blood 
• 
Serum concentrations of IL-6 and other cytokines  
Exploratory Endpoints: 
• 
 
 
 
 
 
 
 
 
 
 
 
Methodology: This is a global, multicenter, open-label, Phase 1/2 study. The study will be conducted 
in 3 parts: Part A, a dose-escalation monotherapy part; Part B, a dose-expansion monotherapy part; and 
Part C, a combination therapy part with pembrolizumab, as seen in the figure below. An Extension 


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Phase is planned for subjects completing or who have completed 1 year of treatment in Part B or in 
Part C.
Figure 1: Overall Study Design Schematic 
A)
B)


 
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Abbreviations: L1=ligand-1, EOT=End of Treatment, NSCLC=non–small-cell lung cancer, PD-1=programmed 
death receptor-1, RCC=renal cell carcinoma, SCCHN=squamous cell carcinoma of the head and neck, TBD=to 
be determined. 
a Rollover subjects from Part A or Part B to Part C need to complete 1 year of treatment in Part C before entering 
the Extension Phase.  
b Subjects in Part C are eligible to receive combination treatment for a maximum of 2 years of treatment in total 
(the initial phase plus the Extension Phase of Part C). Subjects may continue ALKS 4230 as a monotherapy 
beyond the maximum of 2 years of treatment — both in Part B by continuing treatment or in Part C by 
switching to monotherapy. 
Note (Figure 1 A): If a dose higher than 6 μg/kg of ALKS 4230 is found to be tolerable for Part A, that dose may 
be used in Part B or Part C. 
 
Part A 
In the dose-escalation part of the study, subjects with advanced solid tumors will receive ALKS 4230 
by IV administration daily for 5 days, followed by a period off treatment in repeating cycles. During 
Cycle 1, the period off treatment will be 9 days, resulting in a cycle length of 14 days (2 weeks). Cycle 
2 and subsequent cycles will have a period off treatment of 16 days, resulting in a cycle length of 
21 days (3 weeks) for each cycle. For the first 2 treatment cycles, subjects will receive ALKS 4230 as 
inpatients at a medical facility with access to medical support measures and to the intensive care unit, if 
needed. In the absence of DLTs, subjects who remain in the study may receive subsequent doses of 
ALKS 4230 on an outpatient basis. 
In dose escalation, cohorts in the study will use a standard 3+3 study design with 3 to 6 subjects per 
cohort to receive ALKS 4230 at dose levels described in Figure 1. The starting dose of 0.1 µg/kg/day 
was selected based on the minimal anticipated biologic effect level. Doses in subsequent cohorts will 
be increased until the optimal biologic dose is identified or the maximum tolerated dose is reached. 
Additional dose levels will be considered if the RP2D or maximum tolerated dose (MTD) has not been 
reached within the proposed dose range. 
During dose escalation, each cohort will be evaluated for safety and tolerability using a 3+3 study 
design with allowance for over-enrollment with 4 to 7 subjects and a minimum of 3 evaluable subjects 
per cohort to receive IV ALKS 4230 at the specified dose and schedule. If none of the 3 subjects 
experiences a DLT, then the next dose level will open for enrollment. If 1 of the 3 subjects experiences 
a DLT, then 3 additional subjects will be enrolled at the same dose level. If no additional DLTs are 
observed, then the next dose level will open for enrollment. 
If 2 or more subjects experience DLTs at a dose level, no further dose escalations will occur. One or 
more lower dose level(s) may be tested in search of the MTD, defined as the dose level immediately 
below that in which ≥2 of 6 subjects experience DLTs. Prior to any dose escalation, a teleconference of 
the Safety Review Committee (SRC), to include at a minimum the study investigators who have 
enrolled subjects and the Sponsor’s Medical Monitor, will be convened to review the safety data from 
the current cohort and to decide if dose escalation is warranted. An interim review of the safety data to 
guide the selection of the RP2D is planned prior to the start of Part B of the study using data from 
subjects enrolled in Part A. 
 
Part B 
After the RP2D is determined, the second part of the study (ie, Part B) will begin. In this part of the 
study, up to 41 subjects with melanoma and up to 41 subjects with RCC may be enrolled to receive 
ALKS 4230 at the RP2D. Enrollment to these cohorts will follow a partial response (unconfirmed) 
Simon’s two-stage design enrollment as outlined below. Response assessments will be based on the 
RECIST guidelines. 


 
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Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
Expansion Cohort B1: Refractory 
RCC 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Expansion Cohort B2: Refractory 
Melanomaa 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Abbreviations: CR=complete response, PR=partial response, RCC=renal cell carcinoma. 
a No more than 5 ocular melanoma subjects may be enrolled into this cohort. 
 
Part C 
In the third part of the study (Part C), subjects will receive ALKS 4230 in combination with 
pembrolizumab. Part C will run independently of and concurrently with monotherapy Part A and 
Part B.  
A 3- to 6-subject run-in phase will be utilized to assess the safety of ALKS 4230 in combination with 
pembrolizumab. During the safety run-in phase, subjects may be enrolled with any tumor type as 
described in the nonrollover cohorts. Rollover subjects (Cohort 4) are not eligible to participate in the 
safety run-in phase of Part C.  
During the safety run-in phase, the first 3 subjects will receive ALKS 4230 at the dose level of 
1 µg/kg/day. The first subject enrolled at the 1 µg/kg/day dose level will be monitored as a sentinel 
subject. This sentinel subject will be observed for safety for a period of 7 days (the sentinel period) 
from first dose of ALKS 4230. If the sentinel subject tolerates treatment adequately during this period, 
then up to 2 additional subjects may be enrolled into the 1 µg/kg/day dose level. If all 3 subjects 
tolerate therapy adequately through their first 21-day cycle as assessed by the SRC, then the study will 
progress to the 3 µg/kg/day dose level. At the discretion of the SRC, an additional 3 subjects may be 
enrolled at the 1 μg/kg/day dose level to further assess safety prior to opening enrollment at the 
3 μg/kg/day dose level.  
Once the safety run-in phase at the 1 µg/kg/day dose level is complete and the SRC has agreed to 
proceed to the 3 µg/kg/day dose level, the first subject will be enrolled at the 3 µg/kg/day dose level 
and will be observed for 7 days as a sentinel subject. If this subject tolerates treatment adequately for 
7 days, then up to 2 additional subjects may be enrolled in the following week. If the second and third 
subjects tolerate the 3 µg/kg/day dose level adequately for 7 days, then 3 additional subjects can be 
enrolled beginning the following week.  
If the first 6 subjects tolerate therapy adequately for their first 21-day cycle as assessed by the SRC, 
then enrollment into expansion Cohorts C1, C2, C3, and C4 will be open without restriction in the rate 
of enrollment at the dose determined by the SRC. 
Up to 20 subjects will be enrolled into each of Cohorts C1, C2, and C3 based on their tumor type and 
prior treatment with programmed death receptor-1/programmed death ligand-1 (PD-L1) pathway 
inhibitors as described in the inclusion criteria. Subjects with RCC or melanoma will not be eligible for 
enrollment in Cohorts C1, C2, or C3. Subjects on ALKS 4230 monotherapy in Part A or Part B who 
have experienced disease progression after a minimum of 2 cycles or stable disease (SD) after a 
minimum of 4 cycles and who are expected to tolerate treatment with combination therapy are eligible 
for treatment in Part C, Cohort C4. Subjects who have partial response (PR) or complete response (CR) 
on monotherapy are ineligible to rollover unless subsequently demonstrating progressive disease. 
Subjects will receive 200 mg of pembrolizumab every 3 weeks in combination with ALKS 4230 by IV 
administration daily for 5 days, followed by a period off treatment of 16 days, resulting in a cycle 
length of 21 days (3 weeks) for each cycle.  


 
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Once a RP2D is determined for monotherapy, enrollment into Cohorts C5, C6, and C7 will open. 
Should monotherapy doses above 6 µg/kg/day ALKS 4230 be shown to be tolerated, then the dose of 
ALKS 4230 in the combination arms may be increased. In Cohorts C5, C6, and C7, up to 53 subjects 
with melanoma, up to 42 subjects with non–small-cell lung cancer (NSCLC), and up to 36 subjects 
with squamous cell carcinoma of the head and neck may be enrolled to receive ALKS 4230 in 
combination with pembrolizumab at the ALKS 4230 RP2D. Enrollment to these cohorts will follow a 
PR (unconfirmed) Simon’s two-stage enrollment as outlined below. Response assessments will be 
based on the RECIST and iRECIST guidelines. 
  
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
C5: Melanoma 
40% 
55% 
27 
≥12 PR/CR 
26 
53 
C6: NSCLC 
13% 
27% 
18 
≥3 PR/CR 
24 
42 
C7: SCCHN 
15% 
30% 
17 
≥3 PR/CR 
19 
36 
Abbreviations: CR=complete response; NSCLC=non–small-cell lung cancer; PR=partial response; 
SCCHN=squamous cell carcinoma of the head and neck 
If the monotherapy RP2D is determined by the SRC to be 6 μg/kg/day or above, intrapatient dose 
escalation may be considered for subjects in Cohorts C1, C2, C3, and C4 who had been assigned to the 
1 μg/kg/day or 3 μg/kg/day dose levels and had adequately tolerated the combination therapy. 
Planned Number of Subjects for Part C 
Expansion Cohort: Tumor (Setting) 
Number of Subjects 
C1: PD-1/L1 unapproved tumor typesa 
Up to 20 
C2: PD-1/L1 approved tumor types (PD-1/L1 treatment pretreated)a 
Up to 20 
C3: PD-1/L1 approved tumor types (PD-1/L1 treatment naive)a 
Up to 20 
C4: Monotherapy Rollover 
Not applicable 
C5: Melanoma 
Up to 53 
C6: NSCLC 
Up to 42 
C7: SCCHN 
Up to 36 
Abbreviations: C=Cohort, NSCLC=non–small-cell lung cancer, PD-1/L1=programmed death 
receptor-1/programmed death ligand-1, RCC=renal cell carcinoma, SCCHN=squamous cell carcinoma of the 
head and neck. 
a Subjects with RCC or melanoma are not eligible for enrollment in Cohorts C1, C2, and C3. 
 
Extension Phase (Part B and Part C only) 
An Extension Phase is planned for subjects receiving clinical benefit from the treatment who are 
completing or have completed 1 year of treatment in Part B or in Part C. The Extension Phase will 
allow for assessment of long-term effectiveness, immunogenicity, and safety information in subjects 
receiving ALKS 4230 monotherapy or ALKS 4230 in combination with pembrolizumab, while 
minimizing the burden of repeated assessments for subjects and investigators. 
Subjects completing 1 year of treatment will enter the Extension Phase after Cycle 18. The subjects 
who are already beyond 1 year of treatment will enter the Extension Phase immediately and will start 
following the Schedule of Assessments of the Extension Phase (Table 8). The 1-year treatment period 


 
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before the Extension Phase is non-cumulative, ie, in case of rollover from Part A or Part B to Part C, 
subjects need to complete 1 year of treatment in Part C before entering the Extension Phase. 
Subjects in Part C are eligible to receive combination treatment for a maximum of 2 years of treatment 
in total (the initial phase plus the Extension Phase of Part C). Subjects may continue ALKS 4230 as a 
monotherapy beyond the maximum of 2 years of treatment — both in Part B by continuing treatment 
or in Part C by switching to monotherapy. Subjects will remain on the same dose and schedule when 
entering the Extension Phase. 
Number of Subjects Planned:  
Part A: Approximately 36 to 54 subjects  
Part B: Approximately 42 to 82 subjects with melanoma or RCC 
Part C: Up to 191 subjects  
Main Criteria for Inclusion: Eligible subjects must be aged ≥18 years, and the subjects (or the 
subject’s legal representative) must be willing and able to provide informed consent. In Part A, all 
subjects must have an advanced solid tumor (including lymphomas) that is refractory or intolerant to 
established therapies known to provide clinical benefit for the malignancy in question, or be in the 
judgment of their physician intolerant of established therapies. In Parts B and C, all subjects must have 
an advanced solid tumor and have had the minimum prior lines of therapy as defined by the specific 
cohort into which the subject will enroll. Treatment with prior immunotherapy is permitted, with the 
exception of subjects enrolling into C3, the PD-1/L1 approved tumor types (PD-1/L1 treatment naive) 
cohort, C5, the Melanoma cohort, and C7, the Squamous Cell Carcinoma of the Head and Neck cohort 
who are not permitted to have received prior treatment with an anti-PD-1/L1 therapy. For Part A of the 
study, the subject must have a diagnosis of an advanced solid tumor. For Part B of the study, the 
subject must have a diagnosis of melanoma or RCC and meet other inclusion/exclusion criteria 
specified for Part B cohorts. The subject must be ambulatory with an Eastern Cooperative Oncology 
Group performance status of 0 or 1 and an estimated life expectancy of at least 3 months. Subjects must 
otherwise meet all inclusion/exclusion criteria specified in Section 7. All subjects must be recovered 
from the effects of any previous chemotherapy, immunotherapy, other previous systemic anticancer 
therapy, radiotherapy, or surgery (ie, toxicity no worse than Grade 1 [Grade 2 alopecia and 
treatment-associated peripheral neuropathy are acceptable]). Subjects in the dose-expansion part of the 
study (Part B) and in the combination therapy part of the study (Part C) must have at least one lesion 
that qualifies as a target lesion based on RECIST guidelines. 
Subjects must wait at least 5 half-lives or 4 weeks (whichever is shorter) following prior therapy before 
enrollment into the study. Shorter wait periods may be permitted after discussion with the Medical 
Monitor. Subjects enrolled in the combination therapy part (Part C) of the study must have completed 
the last dose of any broad spectrum antibiotic at least 30 days prior to first dose (Cycle 1, Day 1). 
For enrollment into Parts B and C, subjects must agree to provide archival tumor tissue biopsy 
sample(s), if available. The archival tumor tissue sample does not have to be obtained prior to 
enrollment into the study; however, every effort should be made to submit the archived tissue within 
30 days of study enrollment. 
Subjects should be willing and able to meet contraceptive requirements listed in Section 8.4.2 during 
the study and for 90 days after the last dose (for subjects in Part A and Part B) and 4 months after the 
last dose (for subjects in Part C). Females of childbearing potential must have a negative urine or serum 
pregnancy test within 7 days of the start of treatment, and on Day 1 before the first dose is 
administered.  
For monotherapy expansion cohorts (Part B) and the combination therapy part of the study (Part C), 
subjects must meet the following criteria to enroll into the cohorts identified below. 


 
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Additional Inclusion Criteria for Part B Melanoma Expansion Cohort 
Subjects must have advanced melanoma. Subjects should have received an immune checkpoint 
inhibitor (eg, anti-PD-[L]1 with or without anti-CTLA-4) and, if appropriate, a molecularly targeted 
agent (eg, BRAF inhibitor if BRAF-mut), and no more than one prior regimen of cytotoxic 
chemotherapy. Subjects previously treated with checkpoint inhibitor either as single-agent or in a 
combination regimen should have experienced objective response or SD (by RECIST or iRECIST) as 
best overall response. Subjects with progressive disease as best overall response may be included on a 
case-by-case basis by the Medical Monitor. 
Additional Inclusion Criteria for Part B Renal Cell Carcinoma Expansion Cohort 
Subjects must have advanced RCC. Subjects must have received a PD-1 or PD-L1-immune checkpoint 
inhibitor, either given as a monotherapy or in combination with a CTLA-4 inhibitor or in combination 
with a VEGFR-TKI and no more than two prior lines of systemic therapies, including the checkpoint 
inhibitor-based regimen. Subjects previously treated with checkpoint inhibitor either as single-agent or 
in a combination regimen should have experienced objective response or SD (by RECIST or iRECIST) 
as best overall response. Subjects with progressive disease as best response may be included on a 
case-by-case basis by the Medical Monitor. 
Additional Inclusion Criteria for Expansion Cohort C1: PD-1/L1 Unapproved Tumor Types  
Subjects who have tumors (excluding RCC and melanoma) that have progressed following 
chemotherapy, and whose tumor types are not approved for treatment with pembrolizumab, may be 
entered in Part C, Cohort C1, if they meet the inclusion/exclusion criteria specified. 
Additional Inclusion Criteria for Expansion Cohort C2: PD-1/L1 Approved Tumor Types 
(PD-1/L1 Pretreated): Approved Tumor Types are Based on US FDA Label 
Subjects who have tumor types (excluding RCC and melanoma; subjects with NSCLC should enroll in 
C6 if eligible) that are approved for treatment with pembrolizumab and have progressed on 
anti-PD-1/PD-L1 treatment may be entered in Part C, Cohort C2, if they meet the other 
inclusion/exclusion criteria specified. 
Additional Inclusion Criteria for Expansion Cohort C3: PD-1/L1 Approved Tumor Types 
(PD-1/L1 Treatment Naive): Approved Tumor Types are Based on US FDA Label 
Subjects who have tumors (excluding RCC and melanoma) that have progressed following 
chemotherapy and whose tumor types are approved for treatment with pembrolizumab may be entered 
in Part C, Cohort C3, if they have not received treatment with an anti-PD-1/PD-L1 antibody and if they 
meet the other inclusion/exclusion criteria specified. 
Additional Inclusion Criteria for Expansion Cohort C4: Monotherapy Rollover (Rollover 
Subjects From Part A or Part B) 
Subjects on ALKS 4230 monotherapy in Part A or Part B who have experienced disease progression 
after a minimum of 2 cycles or SD after a minimum of 4 cycles and who are expected to tolerate 
treatment with combination therapy are eligible for treatment in Part C, Cohort C4. Subjects who have 
PR or CR on monotherapy are ineligible to rollover unless subsequently demonstrating progressive 
disease. 
Additional Inclusion Criteria for Expansion Cohort C5: Melanoma 
Subjects with unresectable locally advanced (Stages IIIB, IIIC, and IIID) or distantly metastatic 
(recurrent or de novo Stage IV) invasive cutaneous or mucosal melanoma that is measurable and who 
have not received prior treatment for advanced disease and who meet the other inclusion/exclusion 
criteria may be considered for Part C, Cohort C5. Subjects that are known to be BRAF mutation-
positive are eligible without prior treatment or after failure of BRAF-directed inhibitor therapy. 
Subjects treated with prior adjuvant therapy with approved agents are also eligible, provided they did 
not have a recurrence within the 6 months of completing adjuvant treatment. 


 
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Additional Inclusion Criteria for Expansion Cohort C6: Non–Small-Cell Lung Cancer 
Subjects with Stage IIIB or IV NSCLC who have been treated with anti-PD-1/PD-L1 therapy either as 
single-agent or in combination with a chemotherapy regimen who responded to therapy or who had SD 
before progression after a minimum of 120 days of treatment and who meet the other 
inclusion/exclusion criteria may be considered for Part C, Cohort C6. 
Additional Inclusion Criteria for Expansion Cohort C7: Squamous Cell Carcinoma of the Head 
and Neck 
Subjects with recurrent and/or distantly metastatic squamous cell carcinoma of the head and neck who 
have not received anti-PD-1/PD-L1 therapy and who meet the other inclusion/exclusion criteria 
specified may be considered for Part C, Cohort C7. 
Main Criteria for Exclusion 
The following subjects will be excluded:  
• 
Subjects currently pregnant or breastfeeding or is planning to become pregnant during the 
study period 
• 
Subjects who have an active infection and/or a fever ≥38.5°C (≥101.3°F) within 3 days of 
the first scheduled day of dosing 
• 
Subjects with active or symptomatic central nervous system metastases unless the 
metastases have been treated by surgery and/or radiation therapy and/or gamma knife, the 
subject has been tapered to a dose of 10 mg of prednisone (or equivalent) or less of 
corticosteroids for at least 2 weeks before the first dose, and the subject is neurologically 
stable. 
• 
Subjects with known hypersensitivity to any components of ALKS 4230.  
• 
Subjects who require pharmacologic doses of corticosteroids (greater than 10 mg of 
prednisone daily, or equivalent); however, topical, ophthalmologic, and inhalational 
steroids are permitted.  
• 
Subjects with mean QT interval corrected by the Fridericia Correction Formula values of 
>470 msec (in females) or >450 msec (in males) at screening. Subjects who are known to 
have congenital prolonged QT syndromes; subjects who are on medications known to 
cause prolonged QT interval on standard 12-lead electrocardiogram. 
• 
Subjects who developed Grade ≥3 autoimmune disorders while on prior immunotherapy 
(eg, pneumonitis, nephritis, neuropathy). Subjects who have immune-mediated 
endocrinopathies and are stable on hormone replacement therapy are not excluded. 
Subjects who developed autoimmune disorders of Grade ≤2 may enroll if the disorder has 
resolved and the subject is off systemic steroids for ≥28 days. Subjects who experienced 
autoimmune colitis as a toxicity of prior immunotherapy must undergo screening 
colonoscopy to rule out ongoing inflammation. Vitiligo is not exclusionary. 
• 
Subjects with any other concurrent uncontrolled illness, including mental illness or 
substance abuse, which may interfere with the ability of the subject to cooperate and 
participate in the study; other examples of such conditions would include unstable or 
poorly controlled hypertension; unstable angina; myocardial infarction, or cerebrovascular 
accident within 6 months of study entry; New York Heart Association Grade 3 or 4 
congestive heart failure; chronic obstructive pulmonary disease or diabetes mellitus that 


 
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has required 2 or more hospitalizations in the last year; severe peripheral vascular disease; 
or recent serious trauma. 
• 
Subjects known to be positive for human immunodeficiency virus are excluded. Subjects 
with active tuberculosis or a known history of tuberculosis are excluded. Subjects with 
active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) are excluded, 
however, subjects with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) 
may be enrolled provided that prior testing/known status for HBV DNA is negative. 
Subjects with active hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] 
[qualitative] are detected) are excluded, however, subjects with cured hepatitis C (negative 
HCV RNA prior test/known status) may be enrolled. 
• 
Subjects who are investigational site staff members directly involved in the conduct of the 
trial and their immediate family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Alkermes or Syneos Health employees directly involved 
in the conduct of the study. (Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.) 
• 
Subjects with a known hypersensitivity to any components of pembrolizumab (Part C 
subjects only) 
• 
Subjects who have had a second malignancy within the previous 3 years. This criterion 
does not apply to subjects with an adequately treated basal cell or squamous cell skin 
cancer, carcinoma in situ of the cervix, prostate cancer Gleason score <6 with undetectable 
prostate-specific antigen over the previous 12 months, ductal breast carcinoma in situ with 
full surgical resection. 
• 
Subjects with dyspnea at rest or requiring oxygen therapy 
• 
Subjects with active autoimmune disease requiring systemic treatment within the past 
3 months or documented history of clinically severe autoimmune disease that has required 
systemic steroids and/or immunosuppressive agents. 
• 
Subjects who have received systemic immunomodulatory agents within 28 days prior to 
C1D1. Exceptions may be granted on a case-by-case basis by the Medical Monitor 
• 
Subjects who have received radiotherapy within the last 4 weeks before start of study 
treatment administration, with the exception of limited field palliative radiotherapy at the 
discretion of the Medical Monitor.  
• 
Subjects who have received administration of a live, attenuated vaccine within 4 weeks 
before Cycle 1 Day 1.  
• 
Prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow transplant 
recipients. 
• 
Subjects who have received prior IL-2-based or IL-15-based cytokine therapy. 
Investigational Product, Dosage, Duration, and Mode of Administration:
 
 


 
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Reconstituted ALKS 4230 is administered via a 30-minute IV infusion once daily for 5 consecutive 
days, followed by 9 days off for Cycle 1 (Parts A and B) and 16 days off for all subsequent cycles.  
In Part C, on days where ALKS 4230 is administered in combination with pembrolizumab, 
ALKS 4230 should be administered by infusion 60 (±30) minutes after the completion of 
pembrolizumab infusion. 
Pembrolizumab is to be administered as an IV infusion over 30 minutes in a dose of 200 mg every 
3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible for 
either drug. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted for ALKS 4230 and pembrolizumab (ie, infusion 
time is 30 minutes [-5 minutes/+10 minutes]). 
Pembrolizumab is to be obtained from the study sites’ pharmacies, from commercial supplies, or 
provided by Sponsor. 
 
 
Duration of Treatment: In Parts A and B, Cycle 1 consists of 5 consecutive days of treatment with 
ALKS 4230 followed by 9 days off treatment, for a total of 14 days. Cycle 2 and all subsequent cycles 
of treatment consist of 5 consecutive days of treatment with ALKS 4230 followed by 16 days off 
treatment, for a total of 21 days for each cycle. Subjects may continue additional cycles of treatment 
until evidence of progressive disease, intolerance to ALKS 4230, removal by the Investigator, 
withdrawal of consent, or any other criteria for study removal. 
In Part C, all cycles of treatment consist of pembrolizumab administration every 3 weeks in 
combination with 5 consecutive days of treatment with ALKS 4230 followed by 16 days off treatment, 
for a total of 21 days for each cycle. Subjects may continue additional cycles of treatment until 
evidence of progressive disease, intolerance to ALKS 4230, removal by the Investigator, withdrawal of 
consent, or any other criteria for study removal. For Part C, subjects who discontinue one drug (eg, due 
to unacceptable toxicity that cannot be managed by dose modification) must discontinue the entire 
study treatment. 
In the Extension Phase, the treatment duration of monotherapy with ALKS 4230 may be extended until 
disease progression or until the subject meets any other criteria for treatment discontinuation 
(Section 7.3). Subjects in Part C are eligible to receive combination treatment for a maximum of 
2 years of treatment in total (the initial phase plus the Extension Phase of Part C) for as long as the 
subject appears to be deriving clinical benefit (ie, objective response or SD) and has tolerated therapy 
well. Subjects may continue ALKS 4230 as a monotherapy beyond the maximum of 2 years of 
treatment — both in Part B by continuing treatment or in Part C by switching to monotherapy, at the 
joint discretion of the Investigator and Sponsor and if they do not meet any other criteria for 
discontinuation. 
Antitumor Activity: Tumor assessments will be performed throughout study treatment and analyzed 
using RECIST and iRECIST guidelines. 
Pharmacokinetics/Pharmacodynamics, Immunogenicity, and Other Biomarkers: 
 
 


 
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Statistical Methods: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
TABLE OF CONTENTS ...........................................................................................14 
4. 
LIST OF ABBREVIATIONS.....................................................................................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Nonclinical Pharmacology Evaluation .......................................................................23 
5.1.1. 
In Vitro Primary Pharmacology ..................................................................................23 
5.1.2. 
In Vivo Primary Pharmacology ..................................................................................24 
5.2. 
Nonclinical Pharmacokinetic Evaluation ...................................................................25 
5.3. 
Nonclinical Toxicology Studies .................................................................................26 
5.3.1. 
General Toxicology Studies .......................................................................................26 
5.3.2. 
In Vivo General Toxicology .......................................................................................26 
6. 
STUDY OBJECTIVES ..............................................................................................28 
6.1. 
Primary Objectives .....................................................................................................28 
6.2. 
Secondary Objectives .................................................................................................28 
6.3. 
Exploratory Objectives ...............................................................................................28 
6.4. 
Primary Endpoints ......................................................................................................28 
6.5. 
Secondary Endpoints ..................................................................................................29 
6.6. 
Exploratory Endpoints ................................................................................................29 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30 
7.1. 
Subject Inclusion Criteria ...........................................................................................30 
7.2. 
Subject Exclusion Criteria ..........................................................................................33 
7.3. 
Subject Discontinuation From Treatment ...................................................................35 
7.4. 
Subject Discontinuation From Study ..........................................................................35 
7.5. 
Replacement of Subjects .............................................................................................36 
8. 
STUDY DESIGN .......................................................................................................37 
8.1. 
Overall Study Design and Plan ...................................................................................37 
8.2. 
Schedules of Visits and Assessments .........................................................................51 
8.3. 
Study Procedures Descriptions ...................................................................................64 
8.3.1. 
Informed Consent .......................................................................................................64 
8.3.2. 
Eligibility Review .......................................................................................................65 


 
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8.3.3. 
Demographics and Medical History ...........................................................................65 
8.3.4. 
Prior Medication Review ............................................................................................65 
8.3.5. 
Concomitant Medication Review ...............................................................................65 
8.3.6. 
Vital Signs, Height, and Weight .................................................................................66 
8.3.7. 
Physical Examination .................................................................................................66 
8.3.7.1. 
Screening Airway Evaluation for Subjects With Head and Neck Cancer Only .........66 
8.3.7.2. 
On Study Airway Evaluation for Subjects With Head and Neck Cancer Only ..........66 
8.3.8. 
Standard 12-Lead Electrocardiogram .........................................................................66 
8.3.9. 
Eastern Cooperative Oncology Group Performance Status ........................................67 
8.3.10. 
Laboratory Assessments .............................................................................................67 
8.3.10.1. 
Hematology, Biochemistry, Microbiology, and Urinalysis ........................................67 
8.3.10.2. 
Pregnancy Testing ......................................................................................................69 
8.3.10.3. 
Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Immunophenotype Testing .........................................................................................69 
8.3.11. 
Drug Dispensation and Reconciliation .......................................................................69 
8.3.12. 
Tumor Imaging and Disease Assessments .................................................................69 
8.3.13. 
Adverse Event Monitoring .........................................................................................69 
8.3.14. 
Tumor Tissue Assessments (Optional) .......................................................................70 
8.4. 
Study Requirements and Restrictions .........................................................................70 
8.4.1. 
Inpatient Treatment .....................................................................................................70 
8.4.2. 
Contraception and Pregnancy .....................................................................................70 
8.4.3. 
Concomitant and Prohibited Medications ..................................................................71 
8.4.3.1. 
Premedication .............................................................................................................72 
8.5. 
Definition of End of the Study ....................................................................................72 
8.6. 
Protocol Deviations ....................................................................................................72 
9. 
TREATMENT OF SUBJECTS ..................................................................................73 
9.1. 
Study Drug Dose and Administration .........................................................................73 
9.1.1. 
ALKS 4230 Dosing and Administration ....................................................................73 
9.1.2. 
Pembrolizumab Dosing and Administration ..............................................................73 
9.2. 
Infusion-Related Reactions .........................................................................................74 
9.3. 
Treatment Adherence ..................................................................................................74 
9.4. 
Method of Assigning Subjects to Treatment ..............................................................74 
9.5. 
Blinding ......................................................................................................................74 


 
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9.6. 
Study Drug Dose Adjustments and Stopping Rules ...................................................74 
9.6.1. 
Adverse Events Observed After Dose-Limiting Toxicity Observation Period ..........74 
9.6.2. 
Management of Missed Doses ....................................................................................75 
9.6.3. 
Intrapatient Dose Escalation .......................................................................................75 
9.6.4. 
Cycle Delays ...............................................................................................................75 
9.7. 
Treatment of Toxicities of ALKS 4230 ......................................................................78 
9.8. 
Treatment of Immune-mediated Adverse Events .......................................................79 
9.9. 
Guidance for Measures to Address Hypotension .......................................................79 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................80 
10.1. 
Study Drug ..................................................................................................................80 
10.2. 
Packaging and Labeling ..............................................................................................80 
10.3. 
Storage ........................................................................................................................80 
10.4. 
Handling and Disposal ................................................................................................80 
10.5. 
Accountability .............................................................................................................81 
11. 
ASSESSMENT OF ANTITUMOR ACTIVITY ........................................................82 
12. 
ASSESSMENT OF PHARMACOKINETICS, PHARMACODYNAMICS, 
AND IMMUNOGENICITY .......................................................................................84 
12.1. 
Pharmacokinetics ........................................................................................................84 
12.2. 
Immunogenicity ..........................................................................................................84 
12.3. 
Pharmacodynamics and Biomarkers...........................................................................84 
12.3.1. 
Blood-Based Biomarkers ............................................................................................84 
12.3.2. 
Tumor Tissue Biomarkers ..........................................................................................84 
12.3.2.1. 
Tumor Biopsies ...........................................................................................................84 
12.3.2.2. 
Archived Tumor ..........................................................................................................85 
13. 
ASSESSMENT OF SAFETY .....................................................................................86 
13.1. 
Definition of Adverse Event .......................................................................................86 
13.2. 
Definition of Serious Adverse Event ..........................................................................87 
13.3. 
Relationship to Study Drug ........................................................................................87 
13.4. 
Monitoring and Recording of Adverse Events ...........................................................88 
13.5. 
Reporting of Serious Adverse Events .........................................................................89 
14. 
STATISTICS ..............................................................................................................90 
14.1. 
Determination of Sample Size ....................................................................................90 
14.2. 
General Statistical Methodology ................................................................................91 


 
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14.3. 
Study Populations .......................................................................................................92 
14.3.1. 
Safety Population ........................................................................................................92 
14.3.2. 
Pharmacokinetic and Pharmacodynamic Population ..................................................92 
14.3.3. 
Antitumor Evaluable Population ................................................................................92 
14.4. 
Statistical Analysis ......................................................................................................92 
14.4.1. 
Subject Disposition, Baseline Demographics, and Treatment Characteristics ...........92 
14.4.1.1. 
Subject Disposition .....................................................................................................92 
14.4.1.2. 
Demographics and Baseline Characteristics ...............................................................92 
14.4.1.3. 
Study Treatment ..........................................................................................................92 
14.4.2. 
Antitumor Activity Analyses ......................................................................................92 
14.4.2.1. 
Overall Response Rate ................................................................................................92 
14.4.2.2. 
Immune Overall Response Rate .................................................................................93 
14.4.2.3. 
Disease Control Rate ..................................................................................................93 
14.4.2.4. 
Immune Disease Control Rate ....................................................................................94 
14.4.2.5. 
Duration of Response (Part B and Part C) ..................................................................94 
14.4.2.6. 
Immune Duration of Response (Part B and Part C) ...................................................94 
14.4.2.7. 
Durable Response Rate (Part B and Part C) ...............................................................95 
14.4.2.8. 
Progression-free Survival (Part B and Part C) ............................................................95 
14.4.2.9. 
Immune Progression-free Survival (Part B and Part C) .............................................96 
14.4.3. 
Pharmacokinetic Analyses ..........................................................................................96 
14.4.4. 
Pharmacodynamic Analyses .......................................................................................96 
14.4.5. 
Immunogenicity Analysis ...........................................................................................96 
14.4.6. 
Tissue Biomarker Analysis .........................................................................................97 
14.4.7. 
Safety Analyses ..........................................................................................................97 
14.5. 
Interim Analysis ..........................................................................................................97 
14.6. 
Independent Data Monitoring Committee ..................................................................98 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................99 
15.1. 
Study Monitoring ........................................................................................................99 
15.2. 
Audits and Inspections ................................................................................................99 
15.3. 
Institutional Review Board/Independent Ethics Committee ......................................99 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................100 
16.1. 
Case Report Forms ...................................................................................................100 
16.2. 
Confidentiality of Data .............................................................................................100 


 
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17. 
ETHICAL CONSIDERATIONS..............................................................................101 
17.1. 
Ethics Review ...........................................................................................................101 
17.2. 
Ethical Conduct of the Study ....................................................................................101 
17.3. 
Written Informed Consent ........................................................................................101 
18. 
DATA HANDLING AND RECORD-KEEPING ....................................................103 
18.1. 
Data Capture .............................................................................................................103 
18.2. 
Inspection of Records ...............................................................................................103 
18.3. 
Retention of Records ................................................................................................103 
18.4. 
Use of Information and Publication Policy ..............................................................104 
19. 
REFERENCES .........................................................................................................105 
 
LIST OF TABLES 
Table 1: 
Study Design Overview ..............................................................................................38 
Table 2: 
Simon’s Two-stage Design Enrollment for Subjects in Part B ..................................41 
Table 3: 
Simon’s Two-stage Design Enrollment for Subjects in Part C ..................................42 
Table 4: 
Planned Number of Subjects for Part C ......................................................................42 
Table 5: 
Schedule of Assessments and Study Visits - Part A ...................................................52 
Table 6: 
Schedule of Assessments and Study Visits - Part B ...................................................56 
Table 7: 
Schedule of Assessments and Study Visits - Part C ...................................................59 
Table 8: 
Schedule of Assessments and Study Visits - Extension Phase (Part B and 
Part C) .........................................................................................................................63 
Table 9: 
Eastern Cooperative Oncology Group Performance Status ........................................67 
Table 10: Clinical Laboratory Assessments ...............................................................................68 
Table 11: Blood Draw Time Windows .......................................................................................69 
Table 14: Adverse Event Causality Guidelines ..........................................................................88 
Table 15: Number of Subjects Expected in Each Study Period ..................................................90 
Table 16: Simon’s Two-stage Design Enrollment for Part B .....................................................90 
Table 17: Simon’s Two-stage Design Enrollment for Part C .....................................................91 
 


 
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LIST OF FIGURES 
Figure 1: 
Overall Study Design Schematic ................................................................................44 
Figure 2: 
Part A Dose Escalation Flow Chart ............................................................................45 
Figure 3: 
Treatment Cycle Schematic for Part A, Cycle 1 .........................................................46 
Figure 4: 
Treatment Cycle Schematic for Part A, Cycle 2 and Subsequent Cycles ..................47 
Figure 5: 
Treatment Cycle Schematic for Part B, Cycle 1 .........................................................48 
Figure 6: 
Treatment Cycle Schematic for Part B, Cycle 2 and Subsequent Cycles ...................49 
Figure 7: 
Treatment Cycle Schematic for Part C, Cycle 1 and Subsequent Cycles ...................50 
 


 
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4. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation or Term 
Explanation or Definition 
AE 
adverse event 
ANC 
absolute neutrophil count 
C2D15 
Cycle 2, Day 15 
CD 
cluster of differentiation 
CI 
confidence interval 
Cmax 
maximum drug concentration in serum 
CR 
complete response 
CSA 
Clinical Study Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
standard 12-lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FIH 
first-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
i- 
immune- 
iAE 
immune adverse event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iCR 
immune complete response 
iDCR 
immune disease control rate 
iDOR 
immune duration of response 
IFN 
interferon 
IL-2 
interleukin-2 
IL-2R 
interleukin-2 receptor 
iORR 
immune overall response rate 
iPD 
immune progressive disease 
iPFS 
immune progression-free survival 
iPR 
immune partial response 
IRB 
Institutional Review Board 


 
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Abbreviation or Term 
Explanation or Definition 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
iSD 
immune stable disease 
IV 
intravenous(ly) 
MP 
memory-phenotype 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer [cells] 
NSCLC 
non–small-cell lung cancer 
ORR 
overall response rate 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death ligand-1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
QD 
once daily 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin-2 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SPD 
sum of the products of the two longest perpendicular diameters 
TID 
3 times daily 
Tregs 
regulatory T cells 
ULN 
upper limit of normal 
USP-NF 
United States Pharmacopeia-National Formulary 
WOCBP 
women of childbearing potential 


 
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5. 
INTRODUCTION 
Alkermes Inc. (Alkermes) is developing ALKS 4230 for the treatment of subjects with advanced 
malignancies. 
Cancer is widely recognized as a prominent cause of illness and death. Approximately 
14.1 million cancer cases and 8.2 million cancer deaths occurred in 2012 worldwide (Torre et al, 
2015). It is projected that in the United States in 2015, over 1.6 million new cancer cases will 
arise and over half a million patients will die of the disease (Siegel et al, 2015). 
The potential of immunotherapy to bring clinical benefit to patients with advanced cancer has 
been recognized for over a century, beginning with the demonstration of activity of Coley’s 
toxins, published in 1893 (Parish 2003). The field advanced further during the 1980s and 1990s, 
with the FDA granting approval for interferon-α for the treatment of various malignancies intron 
(Intron A USPI) and interleukin-2 (IL-2, also known as aldesleukin) for the treatment of 
metastatic renal cell carcinoma (RCC) and metastatic melanoma (Proleukin USPI). More 
recently there has been substantial progress in the field through the blockade of immune 
checkpoints using monoclonal antibodies. The first of these to be approved by the FDA was the 
anticytotoxic T-lymphocyte associated protein-4 antibody ipilimumab, approved for patients 
with unresectable or metastatic melanoma in 2011 and more recently in combination with 
nivolumab for patients with unresectable or metastatic melanoma (Yervoy USPI). The 
antiprogrammed death receptor-1 (PD-1) antibodies pembrolizumab and nivolumab were both 
approved in the United States initially for patients with unresectable or metastatic melanoma 
who had already received other FDA-approved therapies and then subsequently for patients with 
unresectable or metastatic melanoma and in certain patients with non–small-cell lung cancer 
(NSCLC; Keytruda [pembrolizumab] USPI; Opdivo [nivolumab] USPI). Opdivo® [nivolumab] 
was recently approved for patients with advanced RCC who have received prior antiangiogenic 
therapy. Despite this progress, many tumors do not respond to PD-1 pathway inhibitor therapy, 
and many subjects who have responded go on to have progression in their tumors. Opportunities 
remain within the field of immunotherapy for novel anticancer agents or novel combinations of 
these agents. Combination of PD-1 pathway inhibition with cytokine therapy such as 
ALKS 4230 might enhance the antitumor effect of anti-PD-1 monotherapy. The first published 
clinical evidence of combination PD-1 pathway inhibition and cytokine therapy came from a 
study of IL-15 superagonist ALT-803 and nivolumab treatment, which yielded encouraging 
antitumor activity in patients with PD-1 pathway inhibitor relapsed and refractory NSCLC 
(Wrangle et al 2018). Several clinical studies (eg, NCT02983045, NCT02523469, 
NCT03388632, and NCT02964078) are currently underway to further assess the safety and 
antitumor activity of combination therapy with these two classes of agents, including a 
combination study of NKTR-214 (a pegylated IL-2) with nivolumab, which has reported 
antitumor responses in immunotherapy treatment naive patients (Diab 2017). 
ALKS 4230 is an engineered fusion protein composed of a circularly permuted IL-2 and IL-2 
receptor (IL-2R) α designed to selectively activate the intermediate-affinity IL-2R, but not the 
high-affinity IL-2R. The intermediate-affinity IL-2R is expressed predominantly on effector 
lymphocytes, which play an important role in driving antitumor immune responses. In contrast, 
IL-2 preferentially activates the high-affinity IL-2R, driving the expansion of high-affinity 
IL-2R-expressing cell types including immunosuppressive CD4+ regulatory T cells (Tregs), which 
limit anticancer activity by recombinant human IL-2 (rhIL-2, aldesleukin). The high-affinity 


 
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IL-2R is also expressed on vascular and pulmonary endothelial cells and may contribute to 
rhIL-2-mediated toxicity via capillary leak syndrome. Thus, selective activation of the 
intermediate-affinity IL-2R by ALKS 4230 has the potential to provide enhanced tumor killing 
as well as improved safety and tolerability. Pharmacology data supports the thesis that 
ALKS 4230 signals through the intermediate-affinity IL-2R leading to the expansion and 
activation of effector cells while minimizing the expansion and activation of immunosuppressive 
CD4+ Tregs. 
ALK4230-A101 is a Phase 1/2 study of ALKS 4230 administered intravenously as monotherapy 
and in combination with pembrolizumab in subjects with advanced solid tumors. 
Based on a minimal anticipated biological effect level dose of 0.1 µg/kg/day and projected 
minimal efficacious dose of 0.7 to 1.6 µg/kg/day, the proposed doses to be evaluated in the 
Phase 1/2 FIH study by cohort escalation design are 0.1, 0.3, 1, 3, 6, 8, 10, 12, and 14 µg/kg/day. 
If the recommended Phase 2 dose (RP2D) has not been reached within the proposed dose range, 
additional dose escalation will be considered. Following the identification of the RP2D, 
ALKS 4230 will be evaluated in a dose-expansion phase as monotherapy (Part B).  
In Part C (the combination therapy part of the study), ALKS 4230 will be evaluated at the 1, 3, 
and 6 μg/kg/day dose levels in combination with pembrolizumab (if a dose higher than 6 μg/kg 
of ALKS 4230 is found to be tolerable for Part A, that dose may be used in Part C). If the data 
from this initial study are promising, it is expected that ALKS 4230 and/or ALKS 4230 in 
combination with pembrolizumab will progress into further Phase 2 and/or Phase 3 studies. 
Depending on the data from Phase 1 or later studies, ALKS 4230 may be further tested in studies 
that combine it with other anticancer agents. 
ALKS 4230 will be studied under IND 128,159. This study will be conducted according to the 
protocol, Good Clinical Practice (GCP) requirements, and other applicable regulatory 
requirements. 
5.1. 
Nonclinical Pharmacology Evaluation 
ALKS 4230 has been studied using in vitro and in vivo nonclinical methods to characterize its 
pharmacology. Results from selected studies are briefly described below. 
5.1.1. 
In Vitro Primary Pharmacology 
ALKS 4230 was designed to selectively bind to and activate the intermediate-affinity IL-2R, and 
not the high-affinity IL-2R. The potency of activation of the intermediate-affinity IL-2R and 
high-affinity IL-2R by ALKS 4230 relative to rhIL-2 was evaluated 
 
 
 
 
 
 


 
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5.1.2. 
In Vivo Primary Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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5.2. 
Nonclinical Pharmacokinetic Evaluation 
The pharmacokinetics (PK) of ALKS 4230 were determined in male cynomolgus monkeys after 
single intravenous (IV) administration (Study Number AK-4230-01) at 0.03, 0.1, or 0.3 mg/kg. 
After a single IV bolus administration, the PK of ALKS 4230 was characterized by a mean 
serum clearance of 11.9 to 16.6 mL/h/kg and mean steady-state volume of distribution of 80 to 
138 mL/kg. The mean elimination half-life ranged from 20 to 34 hours and the mean residence 
time ranged from 6.7 to 8.2 hours. Systemic exposure to ALKS 4230 (maximum drug 
concentration in serum [Cmax] and area under the curve from time zero to infinity) increased with 
increase in dose; the increase in area under the curve from time zero to infinity appeared to be 
slightly less than dose proportional over the dose range of 0.03 to 0.3 mg/kg. 
The toxicokinetics of ALKS 4230 and anti-ALKS 4230 antibody data were determined in cluster 
of differentiation (CD)-1 mice and cynomolgus monkeys as part of the pivotal repeat-dose 
toxicity studies. 
After QD IV (30-second infusion) administration of ALKS 4230 to CD-1 mice for up to 
28 consecutive days in the repeat-dose pivotal toxicity study, ALKS 4230 exposures (Cmax and 
area under the curve from time zero to 24 hours postdose) increased with increase in dose; the 
increase in exposures was generally dose proportional over the dose range of 0.03 to 
0.3 mg/kg/day. No sex difference in ALKS 4230 exposures and no accumulation of ALKS 4230 
was observed in CD-1 mice after repeat-dose administration of ALKS 4230. Overall, 31 out of 
the 90 toxicity animals (34.4%) dosed with ALKS 4230 tested positive for anti-ALKS 4230 
antibodies. The direct impact of anti-ALKS 4230 antibody development on ALKS 4230 
toxicokinetics could not be determined as the presence of anti-ALKS 4230 antibodies were 
evaluated in samples collected from the toxicity animals and not from the toxicokinetic animals. 
After IV (30-minute infusion) administration of ALKS 4230 to cynomolgus monkeys QD for 
35 consecutive days or for a total of 15 doses (3 cycles of daily dosing for 5 days followed by 
9 days of no dosing) in the pivotal repeat-dose toxicity study, ALKS 4230 exposures (Cmax and 
area under the curve from time zero to 24.5 hours postdose) increased with the increase in dose. 
The increase in ALKS 4230 exposures was generally dose proportional over the dose range of 
1 to 30 µg/kg/day evaluated in the daily dosing regimen and over the dose range of 10 to 
300 µg/kg/day evaluated in the cycle dosing regimen with the exception of a greater than dose 
proportional increase in ALKS 4230 exposure from 100 to 300 µg/kg/day in male monkeys. No 
sex difference in ALKS 4230 exposures and no accumulation of ALKS 4230 were observed in 
monkeys after repeat-dose administration of ALKS 4230. Overall, 11 out of the 40 animals 
(27.5%) dosed with ALKS 4230 tested positive for anti-ALKS 4230 antibodies. However, the 
presence of anti-ALKS 4230 antibodies in animals that were positive for anti-ALKS 4230 
antibodies did not appear to impact the ALKS 4230 concentration profile or exposure. Also, the 
prevalence of anti-ALKS 4230 antibodies did not appear to be dose related. 
The starting dose for the ALKS 4230 FIH Phase 1/2 clinical study is proposed to be 0.1 µg/kg 
based upon the minimal anticipated biological effect level approach recommended by the 


 
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regulatory agency ICH Guidance: S9 Nonclinical Evaluation (International Council for 
Harmonisation 2010). This starting dose is projected to result in an immediate postinfusion 
concentration (Cmax) of 0.0031 µg/mL. The projected minimal efficacious dose in humans for 
activation of IL-2R complex ranges from 0.7 to 1.6 µg/kg and is projected to result in a Cmax 
range of 0.016 to 0.038 µg/mL. Therefore, the proposed doses to be evaluated in the FIH 
Phase 1/2 study are 0.1, 0.3, 1, 3, 6, 8, 10, 12, and 14 µg/kg. In comparison, the 
no-observed-adverse-effect–level for the cycle dosing regimen in the pivotal repeat-dose 
toxicology study in monkeys is 100 µg/kg; the observed Cmax on the last day of dosing was 
2.43 µg/mL in males and 2.61 µg/mL in females. In addition, the Cmax at the proposed starting 
dose of 0.1 µg/kg (0.0031 µg/mL) is about 3-fold lower than the lowest concentration of 
ALKS 4230 (0.01 µg/mL) tested in the ProStorm® Cytokine Release Assays at which only slight 
elevations were observed for IL-6, IL-8, and interferon-γ in a small number of donor samples, 
similar to those in the low-response control across the concentration range evaluated. Therefore, 
0.1 µg/kg is considered a safe starting dose for the FIH study. If the maximum tolerated dose 
(MTD) or the RP2D has not been reached within the proposed dose range, additional dose 
escalation will be considered. 
5.3. 
Nonclinical Toxicology Studies 
5.3.1. 
General Toxicology Studies 
The nonclinical toxicology studies were carried out to evaluate ALKS 4230 safety and to inform 
the selection of a safe FIH starting dose. Relevant species selection was contingent on 
exploratory pharmacology work. Species used in the general toxicology program were CD-1 
mice and cynomolgus monkeys for rodent and nonrodent species, respectively. 
Targets/target organs identified in general toxicology studies included lung, liver, and spleen as 
noted with microscopic pathology. Mortality was seen in nonpivotal dose range-finding in CD-1 
mice at 0.6 mg/kg/day, the pivotal CD-1 mouse study at 0.3 mg/kg/day, and in the pivotal 
monkey study at 0.3 mg/kg/day. Clinical observations of hypoactivity, inappetence, and 
gastrointestinal effects (vomiting, soft feces) were noted in monkeys at doses ≥0.3 mg/kg/day. 
Mortality in mice and monkeys was attributed to lung findings of mononuclear cell infiltrate in 
mouse at ≥0.3 mg/kg/day and moderate hemorrhage peribronchial/perivascular in the 1 monkey 
death at 0.3 mg/kg/day. 
5.3.2. 
In Vivo General Toxicology 
In toxicology studies in both mouse and monkey, ALKS 4230 target organs were lung, liver, and 
spleen. Increased lymphocytic and/or mononuclear cell infiltrations were observed in the Good 
Laboratory Practice (GLP) and non-GLP studies in both species. Mononuclear cell infiltrates 
were noted in other tissues as well but without clinical pathology or clinical observations. These 
findings were not considered adverse in animals receiving low doses of ALKS 4230 because 
these animals survived to termination and the extent of cellular infiltration was reduced during 
recovery. In mice treated at higher doses, fatalities were attributed to cellular infiltration in the 
lungs. One female monkey died early in the GLP study. Her death was attributed to moderate 
peribronchial/perivascular hemorrhage in the lung. The no-observed-adverse-effect–level in 
mouse was determined to be 0.1 mg/kg/day. The no-observed-adverse-effect–level in monkey 


 
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was determined to be 0.001/0.03 mg/kg/day for daily dosing and 0.1 mg/kg/day for cyclical 
dosing. 
Systemic exposure is dose-dependent in both animal species. In the GLP monkey study, 
formation of anti-ALKS 4230 antibodies did not alter serum PK or toxicokinetic profiles. 
ALKS 4230 exposure in the GLP studies of mouse and monkey are more than 700-fold higher 
than the exposure that is expected in the FIH Phase 1/2 study at the starting dose of 
0.1 μg/kg/day. This dose is projected to deliver a postinfusion concentration (Cmax) of 
0.0031 μg/mL. 


 
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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objectives 
• To investigate the safety and tolerability of ALKS 4230 and to determine the MTD 
and the RP2D of ALKS 4230 in subjects with advanced solid tumors who are 
refractory or intolerant to therapies known to provide clinical benefit (Part A) 
• To assess the safety profile and characterize antitumor activity by overall response 
rate (ORR) of ALKS 4230 at the RP2D in subjects with melanoma or RCC (Part B) 
• To characterize the safety profile and antitumor activity by ORR of ALKS 4230 
administered IV in combination with pembrolizumab in subjects with advanced solid 
tumors (Part C) 
• To describe the dose-limiting toxicity (DLT) of ALKS 4230 (Part A) 
6.2. 
Secondary Objectives 
• To characterize the clinical PK profile and immunogenicity of ALKS 4230 alone 
(Part A and Part B) and in combination with pembrolizumab (Part C) 
• To investigate the clinical pharmacodynamic effects of ALKS 4230 alone (Part A and 
Part B) and in combination with pembrolizumab (Part C) 
• To describe any antitumor activity and responses observed with ALKS 4230 (Part A) 
• To evaluate duration of response (DOR), durable response rate (DRR), and time to 
response for subjects treated with ALKS 4230 in each of the expansion cohorts 
(Part B) and in combination with pembrolizumab (Part C) 
6.3. 
Exploratory Objectives 
• To describe changes in post-treatment subject blood and/or tumor tissue samples as 
compared with baseline/pretreatment samples (Part B) 
• 
 
 
 
 
 
 
6.4. 
Primary Endpoints 
• The incidence of DLTs from the first dose through the end of the DLT observation 
period (Part A) 
• The incidence and severity of treatment-emergent AEs according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 or higher (Parts A, B, and C) 


 
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• ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
version 1.1 (Eisenhauer et al 2009) (Part B and Part C) 
6.5. 
Secondary Endpoints 
• Serum concentrations of ALKS 4230 and descriptive PK parameters  
• Presence of anti-ALKS 4230 antibodies in serum 
• Immune (i-) ORR (iORR) based on Immune RECIST (iRECIST) guidelines 
(Seymour et al 2017)  
• Disease control rate (DCR) based on RECIST guidelines and immune DCR (iDCR) 
based on iRECIST guidelines  
• DOR based on RECIST guidelines and immune DOR (iDOR) based on iRECIST 
guidelines  
• DRR based on RECIST and immune durable response rate (iDRR) based on iRECIST 
guidelines for Part B and Part C Cohorts C5, C6, C7 only 
• Progression-free Survival (PFS) and immune PFS (iPFS) for Part B and Part C 
Cohorts C5, C6, C7 only 
• Numbers of circulating CD8+ T cells, Tregs, and NK cells in peripheral blood  
• Serum concentrations of IL-6 and other cytokines  
6.6. 
Exploratory Endpoints 
• 
 
 
 
 
 
 
 
 
 
 
 
 


 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The dose-escalation portion of the study (Part A) will enroll subjects with advanced solid tumors. 
In the monotherapy dose-expansion portion of the study (Part B), subjects with melanoma or 
RCC will be enrolled. In the combination therapy part of the study (Part C), subjects will be 
enrolled in to 1 of the 6 predefined cohorts, and some subjects may be enrolled in the rollover 
cohort from Part A or Part B. Each subject must meet all of the inclusion and none of the 
exclusion criteria to participate in this study. 
7.1. 
Subject Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to participate in this study. 
1. The subject or the subject’s legal representative is willing and able to provide written 
informed consent. 
2. The subject is aged ≥18 years. 
3. For the dose-escalation portion of the study, the subject has a diagnosis of an advanced 
solid tumor; for the dose-expansion portion of the study (Part B), the subject has a 
diagnosis of melanoma or RCC. 
4. In Part A, all subjects must have an advanced solid tumor (including lymphomas) that is 
refractory or, in the judgment of their physician, intolerant to established therapies known 
to provide clinical benefit for the malignancy in question. In Parts B and C, all subjects 
must have an advanced solid tumor and have had the minimum prior lines of therapy as 
defined by the specific cohort into which the subject will enroll. Treatment with prior 
immunotherapy is permitted, with the exception of subjects enrolling into C3, the 
PD-1/L1 approved tumor types (PD-1/L1 treatment naive) cohort; C5, the Melanoma 
cohort; and C7, the Squamous Cell Carcinoma of the Head and Neck cohort who are not 
permitted to have received prior treatment with an anti-PD-1/L1 therapy.  
5. Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination 
therapy part (Part C) of the study must have at least one lesion that qualifies as a target 
lesion based on RECIST. 
6. Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination 
therapy part (Part C) of the study must agree to provide archival tumor tissue biopsy 
sample(s), if available. The archival tumor tissue sample does not have to be obtained 
prior to enrollment into the study, however every effort should be made to submit the 
archived tissue within 30 days of study enrollment.  
7. Subjects enrolled in the combination therapy part (Part C) of the study must have 
completed the last dose of any broad spectrum antibiotic at least 30 days prior to first 
dose (Cycle 1, Day 1). 
8. Subject is ambulatory with an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 and an estimated life expectancy of at least 3 months. 
9. Subjects must have adequate hematologic reserve as evidenced by: 
• Absolute neutrophil count (ANC) of ≥1000/µL, 


 
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• Absolute lymphocyte count of ≥500/µL, 
• Platelet count of ≥75,000/µL, and 
• Hemoglobin of ≥9 g/dL (subjects may be transfused to this level if necessary). 
10. Subjects must have adequate hepatic function as evidenced by aspartate transaminase and 
alanine transaminase values ≤3 × the upper limit of normal (ULN) (≤5 × the ULN if the 
liver is known to be involved by metastatic disease) and serum total bilirubin values of 
≤1.5 × ULN (≤2 × ULN for subjects with known Gilbert’s syndrome) for the reference 
laboratory. 
11. Subjects must have adequate renal function as evidenced by a serum creatinine ≤1.5 × the 
ULN for the reference laboratory or a calculated creatinine clearance of ≥60 mL/min by 
the Cockroft-Gault equation. 
12. For subjects with underlying chronic lung disease, and/or lung primary or metastatic 
disease, and/or pleural effusions, room air oxygen saturation must be ≥92%. 
13. Subjects must be recovered from the effects of any previous chemotherapy, 
immunotherapy, other prior systemic anticancer therapy, radiotherapy, or surgery 
(ie, toxicity no worse than Grade 1 [Grade 2 alopecia and treatment-associated peripheral 
neuropathy are acceptable]). 
14. Subjects who have received standard or investigational agents 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 the investigational agent is not known. 
Shorter wait periods may be permitted after discussion with the Medical Monitor. 
15. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum 
or urine) within 7 days of the start of treatment, and on Day 1 before the first dose is 
administered. A woman is considered as a WOCBP (fertile) following menarche and 
until becoming postmenopausal unless permanently sterile. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. See 
Section 8.4.2 for further details regarding pregnancy requirements. 
16. Meets contraceptive requirements defined in the protocol in Section 8.4.2. Women of 
childbearing potential and men (if their sexual partners are WOCBP) must use at least 
two forms of birth control, at least one of which is considered highly effective, 
throughout the study if they are heterosexually active. See Section 8.4.2 for a definition 
of WOCBP and a complete description of contraceptive requirements.  
In addition to the criteria listed above, to participate in Part B or Part C of the study, subjects 
must meet the following Part B or Part C tumor types inclusion criteria to enroll into the cohorts 
identified below. 
Additional Inclusion Criteria for Part B Melanoma Expansion Cohort 
Subjects must have advanced melanoma. Subjects should have received an immune checkpoint 
inhibitor (eg, anti-PD-[L]1 with or without anti-CTLA-4) and, if appropriate, a molecularly 
targeted agent (eg, BRAF inhibitor if BRAF-mut), and no more than one prior regimen of 
cytotoxic chemotherapy. Subjects previously treated with checkpoint inhibitor either as 
single-agent or in a combination regimen should have experienced objective response or stable 


 
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disease (SD; by RECIST or iRECIST) as best overall response. Subjects with progressive disease 
as best response may be included on a case-by-case basis by the Medical Monitor. 
Additional Inclusion Criteria for Part B Renal Cell Carcinoma Expansion Cohort 
Subjects must have advanced RCC. Subjects must have received a PD-1 or PD-L1-immune 
checkpoint inhibitor, either given as a monotherapy or in combination with a CTLA-4 inhibitor 
or in combination with a VEGFR-TKI and no more than two prior lines of systemic therapies, 
including the checkpoint inhibitor-based regimen. Subjects previously treated with checkpoint 
inhibitor either as single-agent or in a combination regimen should have experienced objective 
response or SD (by RECIST or iRECIST) as best overall response. Subjects with progressive 
disease as best response may be included on a case-by-case basis by the Medical Monitor. 
Additional Inclusion Criteria for Expansion Cohort C1: PD-1/L1 Unapproved Tumor 
Types 
Subjects who have tumors (excluding RCC and melanoma) that have progressed following 
chemotherapy, and whose tumor types are not approved for treatment with pembrolizumab, may 
be entered in Part C, Cohort C1, if they meet the inclusion/exclusion criteria specified. 
Additional Inclusion Criteria for Expansion Cohort C2: PD-1/L1 Approved Tumor Types 
(PD-1/L1 Pretreated): Approved Tumor Types Are Based on US FDA Label 
Subjects who have tumor types (excluding RCC and melanoma; subjects with NSCLC should 
enroll in C6 if eligible) that are approved for treatment with pembrolizumab and have progressed 
on anti-PD-1/PD-L1 treatment may be entered in Part C, Cohort C2, if they meet the other 
inclusion/exclusion criteria specified.  
Additional Inclusion Criteria for Expansion Cohort C3: PD-1/L1 Approved Tumor Types 
Cohort (PD-1/L1 Treatment Naive): Approved Tumor Types Are Based on US FDA Label 
Subjects who have tumors (excluding RCC and melanoma) that have progressed following 
chemotherapy and whose tumor types are approved for treatment with pembrolizumab may be 
entered in Part C, Cohort C3, if they have not received treatment with an anti-PD-1/PD-L1 
antibody and if they meet the other inclusion/exclusion criteria specified.  
Additional Inclusion Criteria for Expansion Cohort C4: Monotherapy Rollover (Rollover 
Subjects From Part A or Part B) 
Subjects on ALKS 4230 monotherapy in Part A or Part B who have experienced disease 
progression after a minimum of 2 cycles or SD after a minimum of 4 cycles and who are 
expected to tolerate treatment with combination therapy are eligible for treatment in Part C, 
Cohort C4. Subjects who have partial response (PR) or complete response (CR) on monotherapy 
are ineligible to rollover unless subsequently demonstrating progressive disease. 
Additional Inclusion Criteria for Expansion Cohort C5: Melanoma 
Subjects with unresectable locally advanced (Stages IIIB, IIIC, and IIID) or distantly metastatic 
(recurrent or de novo Stage IV) invasive cutaneous or mucosal melanoma that is measurable and 
who have not received prior treatment for advanced disease and who meet the other 
inclusion/exclusion criteria may be considered for Part C, Cohort C5. Subjects that are known to 
be BRAF mutation-positive are eligible without prior treatment or after failure of BRAF-directed 
inhibitor therapy. Subjects treated with prior adjuvant therapy with approved agents are also 


 
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eligible, provided they did not have a recurrence within the 6 months of completing adjuvant 
treatment. 
Additional Inclusion Criteria for Expansion Cohort C6: Non-Small-Cell Lung Cancer 
Subjects with Stage IIIB or IV NSCLC who have been treated with anti-PD-1/PD-L1 therapy 
either as single-agent or in combination with a chemotherapy regimen who responded to therapy 
or who had SD before progression after a minimum of 120 days of treatment and who meet the 
other inclusion/exclusion criteria may be considered for Part C, Cohort C6. 
Additional Inclusion Criteria for Expansion Cohort C7: Squamous Cell Carcinoma of the 
Head and Neck 
Subjects with recurrent and/or distantly metastatic squamous cell carcinoma of the head and neck 
who have not received anti-PD-1/PD-L1 therapy and who meet the other inclusion/exclusion 
criteria specified may be considered for Part C, Cohort C7. 
7.2. 
Subject Exclusion Criteria 
Each subject must not have any of the following conditions to be qualified to participate in this 
study. 
1. Subject is currently pregnant or breastfeeding or is planning to become pregnant during 
the study period 
2. Subjects with an active infection or with a fever ≥38.5°C (≥101.3°F) within 3 days of the 
first scheduled day of dosing  
3. Subjects with active or symptomatic central nervous system metastases unless the 
metastases have been treated by surgery and/or radiation therapy and/or gamma knife, the 
subject has been tapered to a dose of 10 mg of prednisone (or equivalent) or less of 
corticosteroids for at least 2 weeks before the first dose, and the subject is neurologically 
stable 
4. Subjects with known hypersensitivity to any components of ALKS 4230 
5. Subjects who require pharmacologic doses of corticosteroids (greater than 10 mg of 
prednisone daily, or equivalent); however, topical, ophthalmologic, and inhalational 
steroids are permitted.  
6. Subjects with mean QT interval corrected by the Fridericia Correction Formula values of 
>470 msec (in females) or >450 msec (in males) at screening; subjects who are known to 
have congenital prolonged QT syndromes; or subjects who are on medications known to 
cause prolonged QT interval on ECG. 
7. Subjects who developed Grade ≥3 autoimmune disorders while on prior immunotherapy 
(eg, pneumonitis, nephritis, neuropathy). Subjects who have immune-mediated 
endocrinopathies and are stable on hormone replacement therapy are not excluded. 
Subjects who developed autoimmune disorders of Grade ≤2 may enroll if the disorder has 
resolved and the subject is off systemic steroids for ≥28 days. Subjects who experienced 
autoimmune colitis as a toxicity of prior immunotherapy must undergo screening 
colonoscopy to rule out ongoing inflammation. Vitiligo is not exclusionary.  


 
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8. Subjects with any other concurrent uncontrolled illness, including mental illness or 
substance abuse, which may interfere with the ability of the subject to cooperate and 
participate in the study; other examples of such conditions would include unstable or 
poorly controlled hypertension; unstable angina; myocardial infarction, or 
cerebrovascular accident within 6 months of study entry; New York Heart Association 
Grade 3 or 4 congestive heart failure; chronic obstructive pulmonary disease or diabetes 
mellitus that has required 2 or more hospitalizations in the last year; severe peripheral 
vascular disease; or recent serious trauma. 
9. Subjects known to be positive for human immunodeficiency virus are excluded. Subjects 
with active tuberculosis or a known history of tuberculosis are excluded. Subjects with 
active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) are excluded, 
however, subjects with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) 
may be enrolled provided that prior testing/known status for HBV DNA is negative. 
Subjects with active hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] 
[qualitative] are detected) are excluded, however, subjects with cured hepatitis C 
(negative HCV RNA prior test/known status) may be enrolled. 
10. Subjects who are investigational site staff members directly involved in the conduct of 
the trial and their immediate family members, site staff members otherwise supervised by 
the Investigator, or subjects who are Alkermes or Syneos Health employees directly 
involved in the conduct of the study. (Immediate family is defined as a spouse, parent, 
child, or sibling, whether biological or legally adopted.) 
11. Subjects with known hypersensitivity to any components of pembrolizumab (Part C 
subjects only) 
12. Subjects who have had a second malignancy within the previous 3 years. This criterion 
does not apply to subjects with an adequately treated basal cell or squamous cell skin 
cancer, carcinoma in situ of the cervix, prostate cancer Gleason score <6 with 
undetectable prostate-specific antigen over the previous 12 months, or ductal breast 
carcinoma in situ with full surgical resection. 
13. Subjects with dyspnea at rest or requiring oxygen therapy 
14. Subjects with active autoimmune disease requiring systemic treatment within the past 
3 months or documented history of clinically severe autoimmune disease that has 
required systemic steroids and/or immunosuppressive agents. 
15. Subjects who have received systemic immunomodulatory agents within 28 days prior to 
C1D1. Exceptions may be granted on a case-by-case basis by the Medical Monitor 
16. Subjects who have received radiotherapy within the last 4 weeks before start of study 
treatment administration, with the exception of limited field palliative radiotherapy at the 
discretion of the Medical Monitor.  
17. Subjects who have received administration of a live, attenuated vaccine within 4 weeks 
before Cycle 1 Day 1.  
18. Prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow 
transplant recipients. 


 
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19. Subjects who have received prior IL-2-based or IL-15-based cytokine therapy. 
7.3. 
Subject Discontinuation From Treatment 
A subject may choose to withdraw or may be discontinued from treatment at any time if the 
subject, Investigator, or Sponsor determines that it is not in the best interest of the subject to 
continue participation. Reasons for withdrawal or discontinuation include: 
• Unacceptable toxicity that cannot be managed by dose modification 
• Pregnancy 
• Immune confirmed progressive disease (iCPD) by iRECIST or clinical progression 
(worsening of symptoms or declining performance status) 
• Severe noncompliance as judged by the Investigator and/or Sponsor 
• Study terminated by Sponsor 
• Subject request (Note: All reasonable efforts should be made to encourage subjects to 
remain on study for follow-up evaluations even if they withdraw from treatment) 
• Physician’s decision 
• Death 
For Part C, subjects who discontinue 1 drug (eg, due to unacceptable toxicity that cannot be 
managed by dose modification) must discontinue the entire study treatment. 
Subjects who request to discontinue treatment will be asked to continue the study visits and 
assessments as outlined in the Schedule of Assessments (Table 5, Table 6, Table 7, and Table 8). 
The ET/EOT visits must be completed for all subjects regardless of whether they actually return 
to the clinic for those visits. However, if a subject completes Cycle 9 and is then lost to 
follow-up or withdraws consent, the site must complete the ET/EOT as well as end of study 
(EOS) CRFs accordingly. 
7.4. 
Subject Discontinuation From Study 
Subjects may be discontinued from the study for any of the following reasons: 
• Withdrawal of consent by the subject, who is at any time free to discontinue his or her 
participation in the study 
• Death 
• Lost to follow-up 
• Sponsor decision to terminate study 
If a subject withdraws or is discontinued from the study for any reason, any ongoing 
treatment-related AEs will be followed until resolution, until deemed stable by the Investigator, 
or until the subject is deemed by the Investigator to be lost to follow-up.  
In the event that a subject chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s 


 
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rights. Enrolled subjects are to be asked to return to the clinic for an early termination visit. The 
early termination visit should be scheduled as close as possible to the subject’s last dose and will 
mimic the assessments scheduled to be conducted at the end of treatment (EOT) visit. Subjects 
who withdraw from or are discontinued from the study will also be asked to complete the safety 
follow-up visits. The EOS visits must be completed for all subjects regardless of whether they 
actually return to the clinic for those visits. For example, if a subject completes Cycle 9 and is 
then lost to follow-up or withdraws consent, the site must still complete the EOS CRF 
accordingly. 
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone to assess as many safety and antitumor activity parameters as possible. If a 
subject is lost to follow-up, attempts should be made to contact the subject to determine the 
reason for discontinuation. For subjects who are lost to follow-up, at least 3 documented 
attempts, including one via certified mail, should be made to contact the subject before 
considering the subject lost to follow-up. 
The Investigator must maintain a record of all subjects who fail to complete the study. A full 
explanation of the reason for study withdrawal or discontinuation will be made on the 
appropriate electronic case report form (eCRF). The reason for discontinuation will be 
documented. 
7.5. 
Replacement of Subjects 
In the dose-escalation part of the study, subjects without a DLT who receive fewer than 10 doses 
through Cycle 2, Day 15 (C2D15) will be considered unevaluable for DLT assessment and will 
be replaced at the same dose level if the minimum number of evaluable subjects has not been 
reached for the cohort. However, the subject may remain in the study if the Investigator feels the 
risk/benefit ratio is acceptable. There will be no replacements of subjects other than subjects who 
are considered unevaluable for DLT assessment. 
Subjects who discontinue for any reason, including disease progression, prior to the completion 
of the C2D15 visit in the dose-expansion part of the study (Part B) or in the combination therapy 
part of the study (Part C) will be replaced.  
Data from subjects who are replaced will be included in the data analysis. 


 
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8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
This is a global, multicenter, open-label, sequential groups Phase 1/2 study. The study will have 
three parts: Part A, a dose-escalation monotherapy part; Part B, a dose-expansion monotherapy 
part; and Part C, a combination therapy part with pembrolizumab.  
In Part A of the study, subjects with advanced solid tumors will receive ALKS 4230 by IV 
administration daily for 5 days, followed by a period off treatment in repeating cycles. During 
Cycle 1, the period off treatment will be 9 days, resulting in a cycle length of 14 days (2 weeks). 
Cycle 2 and subsequent cycles will have a period off treatment of 16 days, resulting in a cycle 
length of 21 days (3 weeks). For the first 2 treatment cycles, subjects will receive ALKS 4230 as 
inpatients at a medical facility with access to medical support measures and to the intensive care 
unit, if needed. In the absence of DLTs, subjects who remain in the study may receive 
subsequent doses of ALKS 4230 on an outpatient basis. 
In dose escalation, cohorts in the study will use a standard 3+3 study design with 3 to 6 subjects 
per cohort to receive ALKS 4230 at dose levels described in Figure 1. The starting dose of 
0.1 µg/kg/day was selected based on minimal anticipated biological effect level. Doses in 
subsequent cohorts will be increased according to Table 1 until stopped for DLTs or an MTD is 
reached. Additional dose levels will be considered if the RP2D or MTD has not been reached 
within the proposed dose range.  
During dose escalation, each cohort will be evaluated for safety and tolerability using a 
3+3 study design with allowance for over-enrollment with 4 to 7 subjects and a minimum of 
3 evaluable subjects per cohort to receive IV ALKS 4230 at the specified dose and schedule. If 
none of the 3 subjects experiences a DLT, then the next dose level will open for enrollment. If 
1 of the 3 subjects experiences a DLT, then 3 additional subjects will be enrolled at the same 
dose level. If no additional DLTs are observed, then the next dose level will open for enrollment. 
If 2 or more subjects experience DLTs at a dose level, no further dose escalations will occur. 
One or more lower dose level(s) may be tested in search of the MTD, defined as the dose level 
immediately below that in which ≥2 of 6 evaluable subjects experience DLTs. Prior to any dose 
escalation, a teleconference of the Safety Review Committee (SRC), to include at a minimum the 
study investigators who have enrolled subjects and the Sponsor’s Medical Monitor, will be 
convened to review the safety data from the current cohort and to decide if dose escalation is 
warranted. 


 
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Table 1: 
Study Design Overview 
Portion of the Study 
Cohort 
ALKS 4230 
Dose 
(µg/kg/day) 
Dose Escalation (Part A)a 
1 
0.1 
2 
0.3 
3 
1 
4 
3 
5 
6 
6 
8 
7 
10 
8 
12 
9 
14 
Dose Expansion (Part B) 
(+ Extension Phaseb) 
Melanomaa 
RP2D 
RCC 
RP2D 
Combination Therapy 
(Part C) 
(+ Extension Phaseb) 
ALKS 4230 1 μg/kg/day safety run-in 
1 
ALKS 4230 3 μg/kg/day safety run-in 
3 
C1:PD-1/L1 unapproved tumor types 
3c 
C2: PD-1/L1 approved tumor types (PD-1/L1 
pretreated) 
3c 
C3: PD-1/L1 approved tumor types (PD-1/L1 
treatment naive) 
3c 
C4: Rollover 
3c 
C5: Melanoma 
6c 
C6: NSCLC 
6c 
C7: SCCHN 
6c 
Abbreviations: DLT=dose-limiting toxicity, NSCLC=non–small-cell lung cancer, PD-1=programmed death 
receptor-1, PD-L1=programmed death ligand-1, RCC=renal cell carcinoma, RP2D=recommended Phase 2 dose, 
SCCHN=squamous cell carcinoma of the head and neck, TBD=to be determined. 
a No more than 5 ocular melanoma subjects may be enrolled into this cohort. 
b For subjects receiving clinical benefit from the treatment who are completing or have completed 1 year of 
treatment in Part B or Part C. Rollover subjects from Part A or Part B to Part C need to complete 1 year of 
treatment in Part C before entering the Extension Phase. 
c A subject’s ALKS 4230 dose may be reduced by one dose level as needed at the discretion of the Investigator. 
If a subject without a DLT receives fewer than 10 doses before completing the C2D15 visit, the 
subject will be replaced, unless the minimum number of evaluable subjects for the cohort has 
been reached. 


 
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If dose escalation is not felt to be warranted, an intermediate dose between the current dose and 
the prior dose may be explored. Alternative dosing frequency (dosing less than 5 consecutive 
days in each treatment cycle) may also be explored depending on safety, PK, and 
pharmacodynamic observations during the dose-escalation portion of the study. 
Dose-limiting toxicity will be defined by any of the following events possibly, probably, or 
definitely related to ALKS 4230 that are observed during the interval from Cycle 1, Day 1 
through C2D15: 
• Grade 4 Neutrophil Count Decreased (neutropenia) that has not recovered to Grade 2 
(≥1000 cells/µL) within 15 days of the start of the cycle or requires an urgent 
intervention (eg, use of hematopoietic colony-stimulating factors) or is associated 
with clinically significant infection. Dosing with ALKS 4230 in the current cycle will 
not be stopped due to neutropenia in the absence of urgent intervention or clinically 
significant infection.  
• Febrile neutropenia (ANC <1000 cells/µL with temperature >38.3°C [100.9°F]) that 
persists for more than 48 hours or requires an urgent intervention (eg, use of 
hematopoietic colony-stimulating factors) or is associated with clinically significant 
infection 
• CTCAE Grade 4 thrombocytopenia that does not recover to Grade ≤2 within 15 days 
of the start of the treatment cycle  
• Thrombocytopenia equivalent to a platelet count <30,000 with clinically significant 
bleeding 
• Any Grade 3 cardiac or central nervous system toxicity 
• Liver transaminase elevation higher than 8 × ULN that does not recover to Grade ≤2 
or baseline within 1 week or total bilirubin higher than 6 × ULN that does not recover 
to Grade ≤2 or baseline within 1 week 
• Grade 4 hypoalbuminemia 
• Fever >40°C (>104°F) sustained for >24 hours 
• Hypotension requiring the use of pressors (eg, phenylephrine or dopamine, 
administered for the purpose of increasing blood pressure) or prolonged 
hospitalization (>48 hours) for hypotension requiring medical intervention 
• Grade 3 or higher electrolyte abnormalities that do not recover to Grade ≤1 within 
48 hours following medical management 
• Increase in amylase or lipase that meets one of the following criteria: 
− Asymptomatic Grade 4 elevation 
− Asymptomatic Grade 3 elevation that does not resolve within 14 days 
− >3× ULN with acute severe abdominal pain (other mild symptoms at Grade 3 will 
not be considered as DLTs) 


 
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• Grade 3 or higher nausea, vomiting, or diarrhea lasting longer than 48 hours despite 
maximum supportive care. 
• Any other Grade 4 nonhematologic toxicity or any other Grade 3 non-hematologic 
toxicity that does not resolve to Grade ≤ 2 within 96 hours, except fatigue or 
anorexia. Fatigue and anorexia are not considered DLTs. 
• Any other toxicity or AE not defined above that results in subject removal from the 
study or discontinuation of dosing by the Investigator. Dose delays during Cycle 2 or 
later are not considered DLTs. 
Any laboratory value that meets the DLT criteria as described above must be confirmed with a 
second laboratory result for DLT criteria to be met. 
Subjects without a DLT who receive fewer than 10 doses through C2D15 will be replaced at the 
same dose level if the minimum number of evaluable subjects has not been reached for the 
cohort. However, the subject may remain in the study if the Investigator feels the risk/benefit 
ratio is acceptable. 
Under certain circumstances an individual subject may be permitted to have his/her dose 
escalated (ie, intrapatient dose escalation). Refer to Section 9.6 for further details. 
Subjects may remain on treatment until criteria for treatment discontinuation are met as 
described in Section 7.3. Subjects may remain on study until criteria for study discontinuation 
are met as described in Section 7.4. Note: all reasonable efforts should be made to encourage 
subjects to remain on study for follow-up evaluations even if they withdraw from treatment. For 
Part C, subjects who discontinue 1 drug (eg, due to unacceptable toxicity that cannot be managed 
by dose modification) must discontinue the entire study treatment. 
In the Extension Phase, the treatment duration of monotherapy with ALKS 4230 may be 
extended until disease progression or until the subject meets any other criteria for treatment 
discontinuation (Section 7.3). Subjects in Part C are eligible to receive combination treatment for 
a maximum of 2 years of treatment in total (the initial phase plus the Extension Phase of Part C) 
for as long as the subject appears to be deriving clinical benefit (ie, objective response or SD) 
and has tolerated therapy well. Subjects may continue ALKS 4230 as a monotherapy beyond the 
maximum of 2 years of treatment — both in Part B by continuing treatment or in Part C by 
switching to monotherapy, at the joint discretion of the Investigator and Sponsor and if they do 
not meet any other criteria for discontinuation. 
An interim review of the safety data to guide the selection of the RP2D is planned prior to the 
start of Part B of the study using data from subjects enrolled in Part A. 
After the RP2D is determined, the second part of the study (ie, Part B) will begin. In this part of 
the study, up to 41 subjects with melanoma (including no more than 5 ocular melanoma subjects) 
and up to 41 subjects with RCC may be enrolled to receive ALKS 4230 at the RP2D. Enrollment 
to these cohorts will follow a PR (unconfirmed) Simon’s two-stage design enrollment as outlined 
in Table 2. Response assessments will be based on the RECIST guidelines. 


 
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Table 2: 
Simon’s Two-stage Design Enrollment for Subjects in Part B 
  
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
Expansion Cohort B1: 
Refractory RCC 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Expansion Cohort B2: 
Refractory Melanomaa 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Abbreviations: CR=complete response, PR=partial response, RCC=renal cell carcinoma. 
a No more than 5 ocular melanoma subjects may be enrolled into this cohort. 
The RP2D will be equal to or less than the MTD and its associated dosing schedule and will be 
selected based on the safety, PK, pharmacodynamics, and preliminary antitumor activity data 
observed during dose escalation. 
An independent data monitoring committee (IDMC) will review accumulating safety and 
efficacy data at regular intervals and monitor overall study conduct beginning in the second stage 
(N2) of Part B cohorts and Part C C5, C6, and C7 cohorts (see Section 14.6 for details). 
In the third part of the study (Part C), subjects will receive ALKS 4230 in combination with 
pembrolizumab. Part C will run independently of and concurrently with monotherapy Part A and 
Part B.  
A 3- to 6-subject run-in phase will be utilized to assess the safety of ALKS 4230 in combination 
with pembrolizumab. During the safety run-in phase, subjects may be enrolled with any tumor 
type as described in the nonrollover cohorts. Rollover subjects (Cohort 4) are not eligible to 
participate in the safety run-in phase of Part C. 
During the safety run-in phase, the first 3 subjects will receive ALKS 4230 at the dose level of 
1 µg/kg/day. The first subject enrolled at the 1 µg/kg/day dose level will be monitored as a 
sentinel subject. This sentinel subject will be observed for safety for a period of 7 days (the 
sentinel period) from first dose of ALKS 4230. If the sentinel subject tolerates treatment 
adequately during this period, then up to 2 additional subjects may be enrolled into the 
1 µg/kg/day dose level. If all 3 subjects tolerate therapy adequately through their first 21-day 
cycle as assessed by the SRC, then the study will progress to the 3 µg/kg/day dose level. At the 
discretion of the SRC, an additional 3 subjects may be enrolled at the 1 μg/kg/day dose level to 
further assess safety prior to opening enrollment at the 3 μg/kg/day dose level. 
Once the safety run-in phase at the 1 µg/kg/day dose level is complete and the SRC has agreed to 
proceed to the 3 µg/kg/day dose level, the first subject will be enrolled at the 3 µg/kg/day dose 
level and will be observed for 7 days as a sentinel subject. If this subject tolerates treatment 
adequately for 7 days, then up to 2 additional subjects may be enrolled in the following week. If 
the second and third subjects tolerate the 3 µg/kg/day dose level adequately for 7 days, then 
3 additional subjects can be enrolled beginning the following week.  
If the first 6 subjects tolerate therapy adequately for their first 21-day cycle as assessed by the 
SRC, then enrollment into expansion Cohorts C1, C2, C3, and C4 will be open without 
restriction in the rate of enrollment at the dose determined by the SRC. 


 
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Up to 20 subjects will be enrolled into each of Cohorts C1, C2, C3 based on their tumor type and 
prior treatment with PD-1/PD-L1 pathway inhibitors as described in the inclusion criteria. 
Subjects with RCC or melanoma will not be eligible for enrollment in Cohorts C1, C2, or C3. 
Subjects on ALKS 4230 monotherapy in Part A or Part B who have experienced disease 
progression after a minimum of 2 cycles or SD after a minimum of 4 cycles and who are 
expected to tolerate treatment with combination therapy are eligible for treatment in Part C, 
Cohort C4. Subjects who have PR or CR on monotherapy are ineligible to rollover unless 
subsequently demonstrating progressive disease. 
Subjects will receive 200 mg of pembrolizumab every 3 weeks in combination with ALKS 4230 
by IV administration daily for 5 days, followed by a period off treatment of 16 days, resulting in 
a cycle length of 21 days (3 weeks) for each cycle. 
Once a RP2D is determined for monotherapy, enrollment into Cohorts C5, C6, and C7 will open. 
Should monotherapy doses above 6 µg/kg/day ALKS 4230 be shown to be tolerated, then the 
dose of ALKS 4230 in the combination arms may be increased. In Cohorts C5, C6, and C7, up to 
53 subjects with melanoma, up to 42 subjects with NSCLC, and up to 36 subjects with squamous 
cell carcinoma of the head and neck may be enrolled to receive ALKS 4230 in combination with 
pembrolizumab at the RP2D. Enrollment to these cohorts will follow a PR (unconfirmed) 
Simon’s two-stage enrollment as outlined below. Response assessments will be based on 
RECIST and iRECIST guidelines. 
Table 3: 
Simon’s Two-stage Design Enrollment for Subjects in Part C 
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
C5: Melanoma 
40% 
55% 
27 
≥12 PR/CR 
26 
53 
C6: NSCLC 
13% 
27% 
18 
≥3 PR/CR 
24 
42 
C7: SCCHN 
15% 
30% 
17 
≥3 PR/CR 
19 
36 
Abbreviations: CR=complete response, NSCLC=non–small-cell lung cancer, PR=partial response, SCCHN=squamous 
cell carcinoma of the head and neck. 
If the monotherapy RP2D is determined by the SRC to be 6 μg/kg/day or above, intrapatient 
dose escalation may be considered for subjects in Cohorts C1, C2, C3, and C4 who had been 
assigned to the 1 μg/kg/day or 3 μg/kg/day dose levels and had adequately tolerated the 
combination therapy. 
Table 4: 
Planned Number of Subjects for Part C 
Expansion Cohort: Tumor (Setting) 
Number of Subjects 
C1: PD-1/L1 unapproved tumor typesa 
Up to 20 
C2: PD-1/L1 approved tumor types (PD-1/L1 treatment pretreated)a 
Up to 20 
C3: PD-1/L1 approved tumor types (PD-1/L1 treatment naive)a 
Up to 20 
C4: Monotherapy Rollover 
Not applicable 
C5: Melanoma 
Up to 53 


 
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Table 4: 
Planned Number of Subjects for Part C (Continued) 
Expansion Cohort: Tumor (Setting) 
Number of Subjects 
C6: NSCLC 
Up to 42 
C7: SCCHN 
Up to 36 
Abbreviations: C=Cohort, NSCLC=non–small-cell lung cancer, PD-1/L1=programmed death 
receptor-1/programmed death ligand-1, RCC=renal cell carcinoma, SCCHN=squamous cell carcinoma of the head 
and neck. 
a Subjects with RCC or melanoma are not eligible for enrollment in Cohorts C1, C2, and C3. 
Extension Phase (Part B and Part C Only) 
An Extension Phase is planned for subjects receiving clinical benefit from the treatment who are 
completing or have completed 1 year of treatment in Part B or in Part C. The Extension Phase 
will allow for assessment of long-term effectiveness, immunogenicity, and safety information in 
subjects receiving ALKS 4230 monotherapy or ALKS 4230 in combination with 
pembrolizumab, while minimizing the burden of repeated assessments for subjects and 
investigators. 
Subjects completing 1 year of treatment will enter the Extension Phase after Cycle 18. The 
subjects who are already beyond 1 year of treatment will enter the Extension Phase immediately 
and will start following the Schedule of Assessments of the Extension Phase (Table 8). The 
1-year treatment period before the Extension Phase is non-cumulative, ie, in case of rollover 
from Part A or Part B to Part C, subjects need to complete 1 year of treatment in Part C before 
entering the Extension Phase.  
Subjects in Part C are eligible to receive combination treatment for a maximum of 2 years of 
treatment in total (the initial phase plus the Extension Phase of Part C). Subjects may continue 
ALKS 4230 as a monotherapy beyond the maximum of 2 years of treatment - both in Part B by 
continuing treatment or in Part C by switching to monotherapy. Subjects will remain on the same 
dose and schedule when entering the Extension Phase. 
An overall schematic of the study design is provided in Figure 1. A dose-escalation flow chart is 
provided in Figure 2. A schematic for Part A Cycle 1 is provided in Figure 3 and for Part A 
Cycle 2 and subsequent cycles in Figure 4. A schematic for Part B Cycle 1 is provided in 
Figure 5 and for Part B Cycle 2 and subsequent cycles in Figure 6. A schematic for Part C is 
provided in Figure 7. 


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Figure 1: 
Overall Study Design Schematic
A)
B)


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Abbreviations: L1=ligand-1, EOT=End of Treatment, NSCLC=non–small-cell lung cancer, PD-1=programmed 
death receptor-1, RCC=renal cell carcinoma, SCCHN=squamous cell carcinoma of the head and neck, TBD=to be 
determined. 
a Rollover subjects from Part A or Part B to Part C need to complete 1 year of treatment in Part C before entering the 
Extension Phase. 
b Subjects in Part C are eligible to receive combination treatment for a maximum of 2 years of treatment in total (the 
initial phase plus the Extension Phase of Part C). Subjects may continue ALKS 4230 as a monotherapy beyond the 
maximum of 2 years of treatment — both in Part B by continuing treatment or in Part C by switching to 
monotherapy.
Note (Figure 1A): If a dose higher than 6 μg/kg of ALKS 4230 is found to be tolerable for Part A, that dose may be 
used in Part B or Part C.
Figure 2: 
Part A Dose Escalation Flow Chart 
Abbreviations: DLT=dose-limiting toxicity, MTD=maximum tolerated dose, RP2D=recommended Phase 2 dose.


 
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Figure 3: 
Treatment Cycle Schematic for Part A, Cycle 1 
 
Abbreviations: D=day. 
* Day 7 only required if subject experiences neutropenia requiring inpatient monitoring per criteria in Section 9.7. Timing of discharge is dependent on subject 
recovery per Section 9.7. 
** There is a +2 day window for the Day 8 visit (Day 8 to 10). 
***Signifies end of Cycle 1; there is no visit associated with Day 14. 


 
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Figure 4: 
Treatment Cycle Schematic for Part A, Cycle 2 and Subsequent Cycles 
 
Abbreviations: D=day. 
* Inpatient treatment not required for Cycles 3 and beyond. Day 7 only required if subject experiences neutropenia requiring inpatient monitoring per criteria in 
Section 9.7. Timing of discharge is dependent on subject recovery per Section 9.7. 
** There is a +2 day window for the Day 8 visit (Day 8 to 10). For Cycle 3 and beyond, Day 8 visits will be virtual/phone visits. 
***Signifies end of Cycle 2; there is no visit associated with Day 21. 


 
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Figure 5: 
Treatment Cycle Schematic for Part B, Cycle 1 
 
Abbreviations: D=day. 
* There is a +2 day window for the Day 8 visit (Day 8 to 10). 
** Signifies end of Cycle 1; there is no visit associated with Day 14. 


 
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Figure 6: 
Treatment Cycle Schematic for Part B, Cycle 2 and Subsequent Cycles 
 
Abbreviations: D=day. 
* There is a +2 day window for the Day 8 visit (Day 8 to 10). For Cycle 3 and beyond, Day 8 visits will be virtual/phone visits. 
** Signifies end of cycle; there is no visit associated with Day 21. 


 
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Figure 7: 
Treatment Cycle Schematic for Part C, Cycle 1 and Subsequent Cycles 
  
Abbreviations: D=day, SD=stable disease. 
a Subjects will continue treatment for as long as they appear to be deriving clinical benefit (ie, objective response or SD) and have tolerated therapy well. 
b Dosing of ALKS 4230 + pembrolizumab 
c Dosing of ALKS 4230 
* There is a +2-day window for the Day 8 visit (Days 8 to 10). For Cycle 3 and beyond, Day 8 visits will be virtual/phone visits. 
** Signifies end of cycle; there is no visit associated with Day 21. 
 


 
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8.2. 
Schedules of Visits and Assessments 
The schedules of visits and assessments for Part A, Part B, and Part C are shown in Table 5, 
Table 6, and Table 7, respectively. The schedule of visits and assessments for the Extension 
Phase of Parts B and C is shown in Table 8. 
 


 
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Table 5: 
Schedule of Assessments and Study Visits - Part A 
Procedure 
Screen-
ing 
 
(D-21 to 
D1) 
CYCLE 1 
(14 DAYS/CYCLE) 
CYCLE 2 
(21 DAYS/CYCLE) 
CYCLE 3 AND BEYOND 
(21 DAYS/CYCLE) 
EOTa 
Safety 
Follow
-Up 
Period 
Follow
-Up 
Assess-
ments 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
1 
2 
3 
4 
5 
6 
7 
8 
15 
1 
2 
3 
4 
5 
8 
15  
 
 
Window (days) 
 
 
 
 
 
 
 
+2 
 
 
 
 
 
 
 
+2 +1 
 
 
 
 
 
+2 +1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Airway evaluationc 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Weight and heightf 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ECOG performance 
score 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
12-lead ECG 
Xh 
Xg 
 
 
 
Xg 
 
 
Xg Xh 
 
 
 
 
 
 
 
 
Xh 
 
 
 
 
 
 
Xh 
 
 
Hematologyi 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
Biochemistryi 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
TSHi 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Serum tumor markersj 
X 
 
 
 
 
 
 
 
 
Xj 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Coagulation paneli 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Urinalysisi 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Tumor imagingl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Xm 


 
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Table 5: 
Schedule of Assessments and Study Visits - Part A (Continued) 
Procedure 
Screen-
ing 
 
(D-21 to 
D1) 
CYCLE 1 
(14 DAYS/CYCLE) 
CYCLE 2 
(21 DAYS/CYCLE) 
CYCLE 3 AND BEYOND 
(21 DAYS/CYCLE) 
EOTa 
Safety 
Follow
-Up 
Period 
Follow
-Up 
Assess-
ments 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
1 
2 
3 
4 
5 
6 
7 
8 
15 
1 
2 
3 
4 
5 
8 
15  
 
 
Window (days) 
 
 
 
 
 
 
 
+2 
 
 
 
 
 
 
 
+2 +1 
 
 
 
 
 
+2 +1 
Administration of 
ALKS 4230 
(mandatory inpatient)n 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
ALKS 4230 (optional 
outpatient)n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
PK samplingo 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
Immunophenotype 
samplingp 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
Cytokine samplingq 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
sampler 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Archival tumor tissue 
samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medicationsu 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsu v 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xw 
 
Abbreviations: ANC=absolute neutrophil count, ECG=standard 12-lead electrocardiogram, ECOG=Eastern Cooperative Oncology Group, EOT=end of 
treatment, IFN=interferon, IL=interleukin, iRECIST=Immune Response Evaluation Criteria in Solid Tumors, NK=natural killer, PK=pharmacokinetic, 
RECIST=Response Evaluation Criteria in Solid Tumors, TNF=tumor necrosis factor, TSH=thyroid-stimulating hormone. 
a End-of-treatment assessments must be completed for all subjects. Once subjects have completed the EOT visit, subjects will be followed for the Safety 
Follow-up Period. 
b Comprehensive physical examination to be done at screening and EOT. Brief physical examination focused on areas of disease or adverse events to be done on 
Day 1 of all treatment cycles. 


 
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c Airway evaluation to be done at times of the physical exam. Subjects with head and neck cancer only. See Section 8.3.7.1 for details of the Screening Airway 
Evaluation and Section 8.3.7.2 for details of the On Study Airway Evaluation. 
d During dosing in Cycle 1 and Cycle 2, vital signs should be collected pretreatment, during the infusion, at end of infusion, and after the infusion at the 
following time points: 0.5 hour (±15 minutes), 1 hour (±15 minutes), 2 hours (±15 minutes), 3 hours (±15 minutes), 4 hours (±15 minutes), 6 hours 
(±15 minutes), 8 hours (±15 minutes), 12 hours (±15 minutes), and 16 hours (±15 minutes). For Cycle 3 and beyond, vital signs are to be collected during the 
following time points: pretreatment, middle of infusion, end of infusion; and after the infusion at the following time points: 0.5 hour (±15 minutes), 1 hour (±15 
minutes), and 2 hours (±15 minutes). Blood pressure, pulse, and respiratory rate should be measured after the subject has been resting in a seated or supine 
position for at least 5 minutes. Section 8.3.6 for further details. 
e These assessments are performed if the subject is hospitalized for monitoring due to neutropenia as per protocol. Subjects who are being monitored for 
neutropenia may be discharged from the hospital when they have recovered per guidance in protocol Section 9.7. 
f Height is to be done only at screening. For the Day 1 visit, weight may be recorded up to 72 hours prior to Day 1. 
g Triplicate ECG to be obtained on Cycle 1 Day 1, Day 5, and Day 8. Timing for ECG assessments is provided in Section 8.3.8. 
h Single ECGs to be obtained at screening, on Day 1 of each subsequent cycle (Cycle 2 and beyond), and at EOT visit. Timing for ECG assessments is provided 
in Section 8.3.8. 
i Blood and urine samples for laboratory assessment will be collected. On dosing days, samples must be collected prior to dosing. For Cycle 1 Day 1, blood and 
urine assessment does not need to be repeated if performed at screening within 7 days of Cycle 1 Day 1. Samples for laboratory assessments may be drawn up 
to 72 hours prior to dosing on Day 1. See Section 8.3.10, Table 10 for assessments. 
j Serum tumor markers as appropriate. After Cycle 2, done only for even-numbered treatment cycles (eg, Cycles 4, 6, etc). See Section 8.3.10 for assessments. 
k A pregnancy test (urine or serum) must be given to all women of childbearing potential before each treatment cycle begins. Pregnancy test results must be 
confirmed as negative before the first dose of each cycle is administered for all cycles. Pregnancy testing may be performed up to 72 hours prior to dosing on 
Day 1. 
l Tumor imaging should include all appropriate radiographic procedures to document the full extent of the subject’s known disease according to RECIST and 
iRECIST guidelines. Assessments are to be done at the end of Cycle 2 but before the next treatment cycle. For subsequent cycles, assessments are to be done at 
the end of each even-numbered treatment cycle (eg, Cycles 4, 6) but before the next treatment cycle. Tumor imaging should be done during the last week of the 
cycle. 
m Subjects will have tumor imaging scans every 9 weeks during the Follow-up Assessment Period (until the subject discontinues from the study or starts a new 
therapy). 
n ALKS 4230 will be given daily for Day 1 to 5 for each treatment cycle. For Cycles 1 and 2 for all dosing levels, all doses will be administered to subjects as 
inpatients at a medical facility with access to medical support measures and to the intensive care unit, if needed. Discharge is typically on Day 6 for Cycles 1 
and 2. Dosing in subsequent cycles may be done as an outpatient. Anytime ALKS 4230 is administered, antipyretics should be administered prior (at least 
15 minutes) to the infusion and should only be withheld at the discretion of the Investigator. 
o PK samples will be collected on Day 1 and Day 5 of Cycle 1 and Cycle 2 at predose, at the completion of the infusion, and 1, 2, 4, 8, and 16 hours after the start 
of the infusion. Additional samples will be collected at predose on Days 2 through 4 and on Day 6 (24 hours post Day 5 dosing), Day 8 (Cycle 1 and Cycle 2), 
and Day 15 (Cycle 2 only). All 16-hour samples and the Day 6 (ie, Day 5, 24 hour) sample are optional. For Cycle 3 and beyond, all PK samples will be 
collected at predose and at the end of the infusion on Days 1, 3, and 5. All PK samples should be drawn from the arm opposite of the arm used to infuse study 
drug. Do not take PK samples from a central line used to infuse study drug. Details regarding PK sample draw windows are provided in Table 11 in 
Section 8.3.10.3. 
p For Cycle 1 and Cycle 2, immunophenotyping samples (quantification of T cell, NK cell, and regulatory T cell counts in peripheral blood) will be collected on 
Day 1 and Day 5 predose and 4 hours (± 15 minutes) after the start of the ALKS 4230 infusion. Additional samples will be collected predose ALKS 4230 on 


 
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Day 2 through Day 4, Day 8 (Cycle 1 and 2), and Day 15 (Cycle 2 only). For Cycle 3 and beyond, Immunophenotype samples will be collected predose on 
Day 1 and Day 5. Immunophenotype draw windows are provided in Section 8.3.10.3. 
q In Cycle 1 and Cycle 2, cytokine samples (for analysis of serum IFN-γ, TNF-α, IL-1, IL-6, and IL-10 levels) will be collected on Day 1 and Day 5 at predose 
and 1, 4, 8, and 16 hours after the start of the infusion. All 16-hour samples are optional. Additional samples will be collected at predose on Days 2 through 4 
and on Day 6, Day 8 (Cycle 1 and Cycle 2), and Day 15 (Cycle 2 only). Details regarding cytokine sample draw windows are provided in Table 11 in 
Section 8.3.10.3. 
r Immunogenicity will be collected predose on Day 1 of each dosing cycle. Immunogenicity draw windows are provided in Section 8.3.10.3. 
s Archival tumor specimen at baseline in subjects with available paraffin-embedded tissue blocks and/or slides. Refer to Section 12.3.2.2 for further details. 
t Tumor biopsy in subjects with accessible lesions (optional, not a study requirement). Refer to Section 12.3.2.1 for further details. 
u Collection of concomitant medication and adverse events can be done by phone if no other assessments are scheduled for the designated day. 
v In the event of Grade 4 neutropenia (where ANC <100/µL) or Grade 3 or higher febrile neutropenia the subject should be hospitalized for monitoring and 
assessments, managed as described in Section 9.7. 
w Subjects will be contacted by the Investigator for phone visits during the Safety Follow-up Period to review any AEs at 30 days after the end of treatment and 
SAEs at 90 days after the end of treatment. SAEs considered by the Investigator to be related to the study drug or study procedures should be recorded. 
 


 
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Table 6: 
Schedule of Assessments and Study Visits - Part B 
Procedure 
Screen-
ing 
 
(D-21 to 
D1) 
CYCLE 1 
(14 DAYS/CYCLE) 
CYCLE 2 
(21 DAYS/CYCLE) 
CYCLE 3 TO START OF 
EXTENSION PHASE * 
(21 DAYS/CYCLE) 
EOTa 
Safety 
Follow
-up 
Period 
Follow-
Up 
Assess-
ments 
Day 
1 
2 
3 
4 
5 
8 
1 
2 
3 
4 
5 
8 
15 
1 
2 
3 
4 
5 
8 
15 
Window (days) 
 
 
 
 
 
+2 
 
 
 
 
 
+2 
+1 
 
 
 
 
 
+2 
+1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Xd 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
Weight and heighte 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ECOG performance score 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
12-lead ECGf 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Hematologyg,h 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
Xd 
X 
X 
 
 
 
X 
 
 
X 
 
 
Biochemistryg 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
Xd 
X 
X 
 
 
 
X 
 
 
X 
 
 
TSHg 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Coagulation panelg 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy testi 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Urinalysisg 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Tumor imagingj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Xk 
Administration of 
ALKS 4230l 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
PK samplingm 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 


 
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Table 6: 
Schedule of Assessments and Study Visits - Part B (Continued) 
Procedure 
Screen-
ing 
 
(D-21 to 
D1) 
CYCLE 1 
(14 DAYS/CYCLE) 
CYCLE 2 
(21 DAYS/CYCLE) 
CYCLE 3 TO START OF 
EXTENSION PHASE * 
(21 DAYS/CYCLE) 
EOTa 
Safety 
Follow
-up 
Period 
Follow-
Up 
Assess-
ments 
Immunophenotype samplingn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
Cytokine samplingo 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Immunogenicity samplep 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Archival tumor tissue sampleq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyr 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ctDNAs 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Prior and concomitant 
medicationst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventst, h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xu 
 
Abbreviations: ANC=absolute neutrophil count, ECG=standard 12-lead electrocardiogram, ECOG=Eastern Cooperative Oncology Group, EOT=end of 
treatment, IFN=interferon, IL=interleukin, iRECIST=Immune Response Evaluation Criteria in Solid Tumors, NK=natural killer, PK=pharmacokinetic, 
RECIST=Response Evaluation Criteria in Solid Tumors, TNF=tumor necrosis factor, TSH=thyroid-stimulating hormone. 
* For procedures beyond 1 year of treatment (ie, after Cycle 18) please refer to the Schedule of Assessments of the Extension Phase (Table 8). The subjects who 
are already beyond 1 year of treatment will enter the Extension Phase immediately and will start following the Schedule of Assessments of the Extension 
Phase. 
a End-of-treatment assessments must be completed for all subjects. Once subjects have completed the EOT visit, subjects will be followed for the Safety 
Follow-up Period. 
b Comprehensive physical examination to be done at screening and EOT. Brief physical examination focused on areas of disease or adverse events to be done on 
Day 1 of all treatment cycles. 
c During dosing, vital signs are to be collected during the following time points: pretreatment, middle of infusion, end of infusion; and after the infusion at the 
following time points: 0.5 hour (±15 minutes), 1 hour (±15 minutes), and 2 hours (±15 minutes). Blood pressure, pulse, and respiratory rate should be measured 
after the subject has been resting in a seated or supine position for at least 5 minutes. See Section 8.3.6 for further details. 
d Only required if biopsy is collected. 
e Height is to be done only at screening. For the Day 1 visit, weight may be recorded up to 72 hours prior to Day 1. 
f Single ECG to be obtained. Timing for ECG assessments is provided in Section 8.3.8. 
g Blood and urine samples for laboratory assessment will be collected. On dosing days, samples must be collected prior to dosing. For Cycle 1 Day 1, blood and 
urine assessment does not need to be repeated if performed at screening within 7 days of Cycle 1 Day 1. Samples for laboratory assessments may be drawn up 
to 72 hours prior to dosing on Day 1. See Section 8.3.10, Table 10 for assessments.  


 
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h In the event of Grade 4 neutropenia (where ANC <100/µL) or Grade 3 or higher febrile neutropenia the subject should be hospitalized for monitoring and 
assessments, managed as described in Section 9.7. 
i A pregnancy test (urine or serum) must be given to all women of childbearing potential before each treatment cycle begins. Pregnancy test results must be 
confirmed as negative before the first dose of each cycle is administered for all cycles. Pregnancy testing may be performed up to 72 hours prior to dosing on 
Day 1. 
j Tumor imaging should include all appropriate radiographic procedures to document the full extent of the subject’s known disease according to RECIST and 
iRECIST guidelines. Assessments are to be done at the end of Cycle 2 but before the next treatment cycle. For subsequent cycles, assessments are to be done at 
the end of each even-numbered treatment cycle (eg, Cycles 4, 6) but before the next treatment cycle. Tumor imaging should be done during the last week of the 
cycle. 
k Subjects will have tumor imaging scans every 9 weeks during the Follow-up Assessment Period (until the subject discontinues from the study or starts a new 
therapy). 
l Anytime ALKS 4230 is administered, antipyretics should be administered prior (at least 15 minutes) to the infusion and should only be withheld at the 
discretion of the Investigator. 
m PK samples will be collected on Day 1 and Day 5 of Cycle 1 and Cycle 2 at predose, at the completion of the ALKS 4230 infusion, and 1, 2, 4, 8, and 16 hours 
after the start of the infusion. Additional samples will be collected at predose on Days 2 through 4 and on Day 6 (24 hours post Day 5 dosing). All 16-hour 
samples, the 8-hour sample on Day 5, and the Day 6 (ie, Day 5, 24 hour) sample are optional. For Cycle 3 and beyond, all PK samples will be collected at 
predose and at the end of the infusion on Days 1, 3, and 5. All PK samples should be drawn from the arm opposite of the arm used to infuse study drug. Do not 
take PK samples from a central line used to infuse study drug. Details regarding PK sample draw windows are provided in Table 11 in Section 8.3.10.3. 
n For Cycle 1 and Cycle 2, immunophenotyping samples (quantification of T cell, NK cell, and regulatory T cell counts in peripheral blood) will be collected on 
Day 1 and Day 5 predose and 4 hours (± 15 minutes) after the start of the ALKS4230 infusion. Additional samples will be collected predose ALKS 4230 on 
Day 2 through Day 4, Day 8 (Cycle 1 and 2), and Day 15 (Cycle 2 only). For Cycle 3 and beyond, immunophenotype samples will be collected predose on Day 
1 and Day 5. 
o Cytokine samples (for analysis of serum IFN-γ, TNF-α, IL-1, IL-6, and IL-10 levels) will be collected on Day 1 and Day 5 at predose and 1, 4, 8, and 16 hours 
after the start of the ALKS 4230 infusion. All 16-hour samples are optional. Additional samples will be collected at predose on Days 2 through 4 and on Day 
15 (Cycle 2 only). Details regarding cytokine sample draw windows are provided in Table 11 in Section 8.3.10.3. 
p Immunogenicity will be collected predose on Day 1 of each dosing cycle. Immunogenicity draw windows are provided in Section 8.3.10.3. 
q Archival tumor specimen at baseline in subjects with available paraffin-embedded tissue blocks and/or slides. Refer to Section 12.3.2.2 for further details. 
r Tumor biopsy in subjects with accessible lesions (optional, not a study requirement). Refer to Section 12.3.2.1 for further details. 
s ctDNA to be collected at screening, Cycle 1 Day 8, Cycle 2 Day 1, Cycle 3 Day 1, and EOT. On dosing days, ctDNA to be collected prior to dosing. 
t Collection of concomitant medication and adverse events can be done by phone if no other assessments are scheduled for the designated day. 
u Subjects will be contacted by the Investigator for phone visits during the Safety Follow-up Period to review any AEs at 30 days after the end of treatment and 
SAEs at 90 days after the end of treatment. SAEs considered by the Investigator to be related to the study drug or study procedures should be recorded. 


 
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Table 7: 
Schedule of Assessments and Study Visits - Part C 
Procedure 
Screen-
ing 
 
(D-21 to 
D1) 
CYCLE 1 
(21 DAYS/CYCLE) 
CYCLE 2 
(21 DAYS/CYCLE) 
CYCLE 3 TO START OF 
EXTENSION PHASE * 
(21 DAYS/CYCLE) 
EOTa 
Safety 
Follow
-up 
Period 
Follow-
Up 
Assess-
ments 
Day 
1 
2 
3 
4 
5 
8 
15 
1 
2 
3 
4 
5 
8 
15 
1 
2 
3 
4 
5 
8 
15 
Window (days) 
 
 
 
 
 
+2 
+1 
 
 
 
 
 
+2 
+1 
 
 
 
 
 
+2 +1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Airway evaluationc 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Xe 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
Weight and heightf 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ECOG performance score 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
12-lead ECGg 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Hematologyh,i  
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Xe 
X 
X 
 
 
 
X 
 
 
X 
 
 
Biochemistryh 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Xe 
X 
X 
 
 
 
X 
 
 
X 
 
 
TSHh 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Serum tumor markersj 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Coagulation panelh 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Urinalysish 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Tumor imagingl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Xm 
Administration of 
ALKS 4230n 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 


 
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Table 7: 
Schedule of Assessments and Study Visits - Part C (Continued) 
Procedure 
Screen-
ing 
 
(D-21 to 
D1) 
CYCLE 1 
(21 DAYS/CYCLE) 
CYCLE 2 
(21 DAYS/CYCLE) 
CYCLE 3 TO START OF 
EXTENSION PHASE * 
(21 DAYS/CYCLE) 
EOTa 
Safety 
Follow
-up 
Period 
Follow-
Up 
Assess-
ments 
Administration of 
Pembrolizumab 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK samplingo 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Immunophenotype samplingp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
Cytokine samplingq 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity sampler 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Archival tumor tissue samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ctDNAu 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Prior and concomitant 
medicationsv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsu ,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xw 
 
Abbreviations: ANC=absolute neutrophil count, ECG=standard 12-lead electrocardiogram, ECOG=Eastern Cooperative Oncology Group, EOT=end of 
treatment, IFN=interferon, IL=interleukin, INR=international normalized ratio, iRECIST=Immune Response Evaluation Criteria in Solid Tumors, NK=natural 
killer, PK=pharmacokinetic, RECIST=Response Evaluation Criteria in Solid Tumors, TNF=tumor necrosis factor, TSH=thyroid-stimulating hormone. 
* For procedures beyond 1 year of treatment (ie, after Cycle 18) please refer to the Schedule of Assessments of the Extension Phase (Table 8). The subjects who 
are already beyond 1 year of treatment will enter the Extension Phase immediately and will start following the Schedule of Assessments of the Extension 
Phase. 
a End-of-treatment assessments must be completed for all subjects. Once subjects have completed the EOT visit, subjects will be followed for the Safety 
Follow-up Period. 
b Comprehensive physical examination to be done at screening and EOT. Brief physical examination focused on areas of disease or adverse events to be done on 
Day 1 of all treatment cycles. 
c Airway evaluation to be done at times of the physical exam. Subjects with head and neck cancer only. See Section 8.3.7.1 for details of the Screening Airway 
Evaluation and Section 8.3.7.2 for details of the On Study Airway Evaluation. 
d In Cycle 1 and Cycle 2, Day 1 vital signs should be collected before pembrolizumab infusion, during pembrolizumab infusion and at end of pembrolizumab 
infusion. Vital signs should also be collected before ALKS 4230 infusion; during the infusion; at end of infusion; and 0.5, 1, 2, 3, 4, and 6 hours (±15 minutes) 
after ALKS 4230 infusion. During all other dosing days of Cycle 1 and Cycle 2, vital signs should be collected before ALKS 4230 infusion; during the 


 
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infusion; at end of infusion; and 0.5, 1, 2, 3, 4, and 6 hours (±15 minutes) after ALKS 4230 infusion. On dosing days in Cycles 3 and beyond, vital signs are to 
be collected before pembrolizumab infusion; middle of ALKS 4230 infusion; end of ALKS 4230 infusion; and 0.5, 1, and 2 hours (±15 minutes) after 
ALKS 4230 infusion. Blood pressure, pulse, and respiratory rate should be measured after the subject has been resting in a seated or supine position for at least 
5 minutes. Section 8.3.6 for further details. 
e Only required if biopsy is collected. 
f Height is to be done only at screening. For the Day 1 visit, weight may be recorded up to 72 hours prior to Day 1. 
g Single ECG to be obtained. Timing for ECG assessments is provided in Section 8.3.8. 
h Blood and urine samples for laboratory assessment will be collected. On dosing days, samples must be collected prior to dosing (predose samples should be 
collected prior to first administration of any study drug, either pembrolizumab or ALKS 4230). For Cycle 1 Day 1, blood and urine assessments do not need to 
be repeated if performed at screening within 7 days of Cycle 1 Day 1. Samples for laboratory assessments may be drawn up to 72 hours prior to dosing on 
Day 1. See Section 8.3.10, Table 10 for assessments. 
i In the event of Grade 4 neutropenia (where ANC <100/µL) or Grade 3 or higher febrile neutropenia the subject should be hospitalized for monitoring and 
assessments, managed as described in Section 9.7. 
j After Cycle 2, done only for even-numbered treatment cycle (eg, Cycles 4, 6, etc). 
k A pregnancy test (urine or serum) must be given to all women of childbearing potential before each treatment cycle begins. Pregnancy test results must be 
confirmed as negative before the first dose of each cycle is administered for all cycles. Pregnancy testing may be performed up to 72 hours prior to dosing on 
Day 1. 
l Tumor imaging should include all appropriate radiographic procedures to document the full extent of the subject’s known disease according to RECIST and 
iRECIST guidelines. For those subjects in the Part C rollover cohort (Cohort 4), who were initially enrolled into study Part A or Part B, the baseline tumor 
image is reset to for Part C will be the screening scan for Part C (not the previous screening scan from Part A or Part B). Assessments are to be done at the end 
of Cycle 2 but before the next treatment cycle. For subsequent cycles, assessments are to be done at the end of each even-numbered treatment cycle (eg, Cycles 
4, 6) but before the next treatment cycle. Tumor imaging should be done during the last week of the cycle. 
m Subjects will have tumor imaging scans every 9 weeks during the Follow-up Assessment Period (until the subject discontinues from the study or starts a new 
therapy). 
n Anytime ALKS 4230 is administered, antipyretics should be administered prior (at least 15 minutes) to the infusion and should only be withheld at the 
discretion of the Investigator.  
o PK samples will be collected on Day 1 and Day 5 of Cycle 1 and Cycle 2 at predose (predose samples should be collected prior to first administration of any 
study drug, either pembrolizumab or ALKS 4230), at the completion of the ALKS 4230 infusion, and 1, 2, 4, and 8 hours after the start of the ALKS 4230 
infusion. Additional samples will be collected at predose on Days 2 through 4. For Cycle 3 and beyond, PK samples will be collected at predose and at the end 
of the ALKS 4230 infusion on Days 1, 3, and 5. All PK samples should be drawn from the arm opposite of the arm used to infuse study drug. Do not take PK 
samples from a central line used to infuse study drug. Details regarding PK sample draw windows are provided in Table 11 in Section 8.3.10.3. The 8-hour PK 
sample on Day 5 is optional. 
p For Cycle 1 and Cycle 2, Immunophenotype samples (quantification of T cell, NK cell, and regulatory T cell counts in peripheral blood) will be collected on 
Day 1 and Day 5 predose (predose samples should be collected prior to first administration of any study drug, either pembrolizumab or ALKS 4230), and 
4 hours (±15 minutes) after the start of the ALKS 4230 infusion. Additional samples will be collected predose on Days 2 through 4 and on Days 8 and 15. For 
Cycle 3 and beyond, immunophenotype samples will be collected predose on Day 1 and Day 5. 
q For Cycle 1 and Cycle 2, Cytokine samples (for analysis of serum IFN-γ, TNF-α, IL-1, IL-6, and IL-10 levels) will be collected on Day 1 and Day 5 at predose 
(predose samples should be collected prior to first administration of any study drug, either pembrolizumab or ALKS 4230), and at 1, 4, and 8 hours after the 


 
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start of the ALKS 4230 infusion. Additional samples will be collected at predose on Days 2 through 4. Details regarding cytokine sample draw windows are 
provided in Table 11 in Section 8.3.10.3. 
r Immunogenicity will be collected predose (predose samples should be collected prior to first administration of any study drug, either pembrolizumab or 
ALKS 4230) on Day 1 of each dosing cycle. Immunogenicity draw windows are provided in Section 8.3.10.3. 
s Archival tumor specimen at baseline in subjects with available paraffin-embedded tissue blocks and/or slides. Refer to Section 12.3.2.2 for further details. 
t Tumor biopsy in subjects with accessible lesions (optional, not a study requirement). Refer to Section 12.3.2.1 for further details. 
u ctDNA to be collected at screening, Cycle 1 Day 8, Cycle 2 Day 1, Cycle 3 Day 1, and EOT. On dosing days, ctDNA to be collected prior to dosing. 
v Collection of concomitant medication and adverse events can be done by phone if no other assessments are scheduled for the designated day. 
w Subjects will be contacted by the Investigator for phone visits during the Safety Follow-up Period to review any AEs at 30 days after the end of treatment and 
SAEs at 90 days after the end of treatment. SAEs considered by the Investigator to be related to the study drug or study procedures should be recorded. 
 


 
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Protocol ALK4230-A101 v 13.0 
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Table 8: 
Schedule of Assessments and Study Visits - Extension Phase (Part B and 
Part C) 
Procedure 
CYCLES IN EXTENSION PHASE  
(21 DAYS/CYCLE) 
X=Every Cycle; (X)=Every 3 Cycles 
EOTa 
Safety 
Follow
-up 
Period 
Follow-Up 
Assessments 
Day 
1 
2 
3 
4 
5 
21 
Window (days) 
 
 
 
 
 
-7 
Physical examinationb 
(X) 
 
 
 
 
 
X 
 
 
Vital signsc 
(X) 
 
 
 
 
 
X 
 
 
Weightd 
X 
 
 
 
 
 
 
 
 
ECOG performance score 
(X) 
 
 
 
 
 
X 
 
 
Single ECG 
(X) 
 
 
 
 
 
X 
 
 
Hematologye f, 
(X) 
 
 
 
 
 
X 
 
 
Biochemistrye 
(X) 
 
 
 
 
 
X 
 
 
Thyroid-stimulating hormonee 
(X) 
 
 
 
 
 
X 
 
 
Coagulation panele 
(X) 
 
 
 
 
 
X 
 
 
Pregnancy testg 
X 
 
 
 
 
 
X 
 
 
Urinalysise 
(X) 
 
 
 
 
 
X 
 
 
Tumor imagingh 
 
 
 
 
 
(X) 
 
 
Xh 
Administration of ALKS 4230i 
X 
X 
X 
X 
X 
 
 
 
 
PK samplingj 
(X) 
 
 
 
 
 
 
 
 
Immunogenicity samplek 
X  
 
 
 
 
 
X 
 
 
ctDNAl 
(X) 
 
 
 
 
 
X 
 
 
Prior and concomitant 
medicationsm 
X 
X 
X 
X 
X 
 
X 
 
 
Adverse eventsm f 
X 
X 
X 
X 
X 
 
X 
Xn 
 
PART C EXTENSION ONLY 
Airway evaluationo 
(X) 
 
 
 
 
 
X 
 
 
Administration of Pembrolizumab 
X 
 
 
 
 
 
 
 
 
Serum tumor markersp 
 
 
 
 
 
(X) 
 
 
 
Abbreviations: ECG=standard 12-lead electrocardiogram, ECOG=Eastern Cooperative Oncology Group, EOT=end 
of treatment, iRECIST=Immune Response Evaluation Criteria in Solid Tumors, PK=pharmacokinetic, 
RECIST=Response Evaluation Criteria in Solid Tumors, Tx=treatment, X=Every Cycle, (X)=Every 3 Cycles. 
a End-of-treatment assessments must be completed for all subjects. Once subjects have completed the EOT visit, 
subjects will be followed for the Safety Follow up Period. 
b Brief physical examination focused on areas of disease or adverse events. 
c In Part B Extension, vital signs are to be collected every 3 cycles: before ALKS 4230 infusion; middle of infusion; 
end of infusion; and 0.5, 1, and 2 hours (±15 minutes) after ALKS 4230 infusion. In Part C Extension, vital signs 


 
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are to be collected every 3 cycles: before pembrolizumab infusion; middle of ALKS 4230 infusion; end of 
ALKS 4230 infusion; and 0.5, 1, and 2 hours (±15 minutes) after ALKS 4230 infusion. Blood pressure, pulse, and 
respiratory rate should be measured after the subject has been resting in a seated or supine position for at least 
5 minutes. See Section 8.3.6 for further details. Only clinically significant results are to be collected in the eCRF. 
d For dose calculation, only clinically significant weight changes are to be collected in the eCRF. 
e Blood and urine samples for laboratory assessment will be collected only if clinically indicated. On dosing days, 
samples must be collected prior to dosing. Samples for laboratory assessments may be drawn up to 72 hours prior 
to dosing on Day 1. See Section 8.3.10 and Table 10 for assessments. Only clinically significant results are to be 
collected in the eCRF. 
f In the event of Grade 4 neutropenia (where absolute neutrophil count <100/µL) or Grade 3 or higher febrile 
neutropenia the subject should be hospitalized for monitoring and assessments, managed as described in 
Section 9.7. 
g A pregnancy test (urine or serum) must be performed and must be negative for all women of childbearing potential 
at the beginning of each cycle prior to dosing on Day 1. Pregnancy testing may be performed up to 72 hours prior 
to dosing on Day 1. Pregnancy test results during the Extension Phase must be recorded in source documentation 
for monitoring purposes and are not required to be collected in the eCRF. 
h Tumor imaging should include all appropriate radiographic procedures to document the full extent of the subject’s 
known disease according to RECIST and iRECIST guidelines. Assessments are to be done every 3 cycles during 
the last week of the cycle (before the next treatment cycle). Subjects will have tumor imaging scans every 
12 weeks during the Follow-up Assessment Period (until the subject discontinues from the study or starts a new 
therapy). 
i Anytime ALKS 4230 is administered, antipyretics should be administered prior (at least 15 minutes) to the 
infusion and should only be withheld at the discretion of the Investigator. 
j PK samples will be collected every 3 cycles. In the first cycle of the Extension Phase, samples will be collected on 
Day 1 at predose (prior to first administration of any study drug, either pembrolizumab or ALKS 4230) and at 
completion of the ALKS 4230 infusion. For other cycles, PK samples will be collected only at the completion of 
the ALKS 4230 infusion. 
k Immunogenicity samples will be collected every 3 cycles at predose (prior to first administration of any study 
drug, either pembrolizumab or ALKS 4230). 
l Every 3 Cycles, on dosing days, ctDNA to be collected prior to dosing. 
m Collection of concomitant medication and adverse events for the remaining cycle days (Days 6 to 21) can be done 
on Day 1 of the next cycle or EOT (as applicable). 
n Subjects will be contacted by the Investigator for phone visits during the Safety Follow-up Period to review any 
adverse events at 30 days after the end of treatment and serious adverse events at 90 days after the end of 
treatment. Serious adverse events considered by the Investigator to be related to the study drug or study procedures 
should be recorded. 
o Airway evaluation to be done at times of the physical exam. Subjects with head and neck cancer only. See 
Section 8.3.7.2 for details of the On Study Airway Evaluation. 
p Serum tumor markers as appropriate; in the same day of tumor imaging. 
8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedules of assessments are 
provided in Table 5, Table 6, Table 7, and Table 8. This study will be conducted in 3 parts: 
Part A, Part B, and Part C. The procedures described in this section will be carried out separately 
for each part. Data cleaning and database lock may occur separately for each part. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and potential benefits will be explained to the subject by the 
Principal Investigator or designated study personnel as outlined in Section 17.3. 
Before the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential subject. 


 
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8.3.2. 
Eligibility Review 
An eligibility review will be conducted by the Investigator at the visits specified in Table 5, 
Table 6, and Table 7 using the subject inclusion criteria in Section 7.1 and exclusion criteria in 
Section 7.2. 
8.3.3. 
Demographics and Medical History 
Subject’s demographic data and medical history will be reviewed and documented at the time 
point specified in Table 5, Table 6, and Table 7. 
The following will be documented for cancer history, if available 
• Primary cancer diagnosis 
• Date of first diagnosis 
• Mutational status if known (eg, MSI/MSS, BRCA1, BRCA2) 
• PD-L1 status if known 
• HPV status if known (subjects with head and neck cancer) 
8.3.4. 
Prior Medication Review 
At the time point(s) specified in Table 5, Table 6, Table 7, and Table 8, prospective subjects are 
to provide a history of all anticancer medications, and a history of all other types of medications 
taken in the last 30 days, including prescription and nonprescription medications, vitamins, and 
supplements. 
The Investigator will record the following data on all medications used by the subject: name, 
dose, regimen, route of administration, start and stop dates, and the indication for use. 
Information collected on prior anticancer medications will be: 
• Information on prior neoadjuvant/adjuvant treatment, if applicable: 
− Agents used in treatment 
• Information on previous anticancer treatments (eg, radiation, systemic therapy, 
surgery): 
− Agents used in all treatments 
• Best response for each line of therapy 
8.3.5. 
Concomitant Medication Review 
Subjects will be asked about all concomitant medications at the time points specified in Table 5, 
Table 6, Table 7, and Table 8, including prescription and nonprescription medications, vitamins, 
and supplements. 
The following data on all medications used by the subject: name, dose, start and stop dates, and 
the indication for use will be recorded. 


 
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8.3.6. 
Vital Signs, Height, and Weight 
Vital signs (ie, blood pressure, pulse, respiratory rate, and body temperature), weight, and height 
will be assessed at the time points specified in Table 5, Table 6, Table 7, and Table 8.  
Blood pressure, pulse, and respiratory rate will be measured after the subject has been resting in 
a seated or supine position for at least 5 minutes. 
8.3.7. 
Physical Examination 
A physical examination will be performed at the time points specified in Table 5, Table 6, 
Table 7, and Table 8. 
8.3.7.1. 
Screening Airway Evaluation for Subjects With Head and Neck Cancer Only 
All subjects whose primary oncologic diagnosis is “head and neck cancer” (regardless of 
histology, ie, whether squamous cell carcinoma of the upper aerodigestive tract, salivary gland 
cancer, sarcoma, etc) and who manifest active loco-regional disease and/or have had a prior 
tracheostomy shall undergo flexible fiberoptic laryngoscopy (FFL) by an appropriately trained 
practitioner at the time of screening, for the purposes of determining airway stability. (FFL 
reports shall be recorded in the respective subject’s chart as a source document.) Subjects whose 
airways are deemed unstable or potentially unstable (threatened) on FFL shall be referred to a 
qualified ear, nose, and throat or head and neck surgeon for further evaluation and clearance or 
definitive management, prior to receiving investigational product(s). 
Subjects with an existing tracheostomy shall be exempted from the above. 
8.3.7.2. 
On Study Airway Evaluation for Subjects With Head and Neck Cancer Only 
While receiving investigational product(s), at the time of each scheduled physical exam (per 
protocol), all subjects whose primary diagnosis is “head and neck cancer” shall undergo pulse 
oximetry and assessment for subjective dyspnea, stridor, tachypnea, and use of accessory 
respiratory muscles. Subjects whose pulse oximetry is less than baseline by 5% or more and/or 
who are deemed to be stridorous, tachypneic and/or dyspneic shall have investigational product 
administration temporarily withheld and shall be referred for emergent formal airway evaluation. 
Tracheostomy removal (decannulation), except for regular cleaning and/or replacement, shall not 
be undertaken during any subject’s (regardless of whether the active oncologic diagnosis is head 
and neck cancer or a different malignancy) time on investigational product(s) unless specifically 
cleared by the Sponsor’s Medical Monitor. 
8.3.8. 
Standard 12-Lead Electrocardiogram 
Part A:  
Triplicate (5 minutes apart) electrocardiograms (ECGs) will be obtained in Cycle 1 at predose, at 
the end of infusion (+15 minutes), and 4 hours (±15 minutes) after the start of the infusion on 
Day 1 and Day 5, and at a single timepoint on Day 8.  
Single ECGs will be obtained at screening, predose on Day 1 of all subsequent cycles (Cycle 2 
and beyond), and at the EOT visit. 


 
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Part B:  
Single ECGs will be obtained at screening, predose on Day 1 of every dosing cycle, and at the 
EOT visit. 
Part C:  
Single ECGs will be obtained at screening, predose (predose assessment is prior to first 
administration of any study drug, either pembrolizumab or ALKS 4230), at the end of 
ALKS 4230 infusion (+15 minutes), and 4 hours (±15 minutes) after the start of ALKS 4230 
infusion on Day 1 and Day 5 of Cycle 1, and predose (predose assessment is prior to first 
administration of any study drug, either pembrolizumab or ALKS 4230) on Day 1 of all 
subsequent cycles (Cycle 2 and beyond), and at the EOT visit. 
8.3.9. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status assesses the subjects’ activity status and will be assessed at the 
time points specified in Table 5, Table 6, Table 7, and Table 8. Possible scores are 0 to 5. 
Descriptions of activity status are presented in Table 9. 
Table 9: 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all predisease 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). 
8.3.10. 
Laboratory Assessments 
8.3.10.1. Hematology, Biochemistry, Microbiology, and Urinalysis 
Blood and urine samples for laboratory assessments will be collected at the time points specified 
in Table 5, Table 6, Table 7, and Table 8. Specific hematology, biochemistry, and urinalysis 
assessments are listed in Table 10. Samples will be collected in accordance with the site’s usual 
procedures and analyzed by the site’s local laboratory for hematology, biochemistry, and 
urinalysis. 
Fasting is not required prior to sample collection for laboratory assessments. 
In the event that any microbiology specimens are obtained for culture, results should be recorded 
in the eCRF. 


 
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Table 10: 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cell count 
• 
Total and differential 
(absolute) white blood cell 
count 
• 
Platelets 
General Chemistry 
• 
Albumin 
• 
Bicarbonate 
• 
Calcium 
• 
Chloride 
• 
Creatine phosphokinase 
• 
Glucose 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
Liver Function Tests 
• 
Alanine transferase 
• 
Alkaline phosphatase 
• 
Aspartate transferase 
• 
Lactic dehydrogenase 
• 
Total bilirubin 
Renal Function Tests 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Bilirubin 
• 
Color and appearance 
• 
Glucose 
• 
Ketones 
• 
Leukocytes 
• 
Nitrite 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal. 
Microscopic examination is not 
needed if urinalysis is abnormal 
for bilirubin, glucose, or ketones. 
Coagulation 
• 
International normalized 
ratio 
• 
Partial thromboplastin time / 
Activated partial 
thromboplastin time 
Microbiology (as Applicable) 
• 
Blood 
• 
Urine 
• 
Other 
 
Thyroid Test 
• 
Thyroid-stimulating 
hormone 
Serum Tumor Marker 
• 
CA125 (ovarian cancer 
subjects only) 
• 
CA19-9 (gastric and 
pancreatic cancer subjects 
only) 
• 
PSA (prostate cancer 
subjects only) 
• 
CEA (colorectal cancer 
subjects only) 
 


 
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8.3.10.2. Pregnancy Testing 
A serum or urine pregnancy test will be administered to all WOCBP at the time points specified 
in Table 5, Table 6, Table 7 and Table 8. At the screening visit, results must be negative for the 
subject to be eligible for the study. Pregnancy test results must be confirmed as negative before 
the first dose of each cycle is administered for all cycles. 
8.3.10.3. Pharmacokinetic, Pharmacodynamic, Immunogenicity, and Immunophenotype 
Testing 
Samples for PK, pharmacodynamic, and immunogenicity testing will be obtained at the time 
points specified in Table 5, Table 6, Table 7, and Table 8. All PK and immunogenicity samples 
should be drawn from the arm opposite of the arm used to infuse study drug. Do not take PK 
samples from a central line used to infuse study drug. Time point draw windows (minutes) are 
summarized in Table 11. 
Table 11: 
Blood Draw Time Windows 
Draw 
Window 
+5 Minutes 
±5 Minutes 
±15 Minutes 
±60 Minutes 
+2 
Days  
(Day 
8-10) 
±24 
Hours 
Draw 
time 
End of 
Infusion 
1 hour after 
infusion 
2, 4, 8, and 
16 hours after 
start of 
infusion* 
Day 6 
(Day 5 + 24 hours)* 
Day 8 
Day 15 
* Denotes an optional sample 
Samples will be collected in accordance with the site’s usual procedures. A Laboratory Manual 
is provided to the sites by the central laboratory with details regarding the collection, handling, 
and shipping of samples for PK, pharmacodynamics, and immunogenicity testing. 
8.3.11. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
administered at the time point(s) specified in Table 5, Table 6, Table 7, and Table 8. 
8.3.12. 
Tumor Imaging and Disease Assessments 
Disease assessments will be made at the time point(s) specified in Table 5, Table 6, Table 7, and 
Table 8. Assessments will be based on Investigator review of the radiographic or photographic 
images as defined by RECIST and iRECIST. Tumor images will be collected and stored 
centrally. Centralized readings may be used to assess scans beginning in the second stage (N2) of 
Part B cohorts and Part C C5, C6, and C7 cohorts. 
8.3.13. 
Adverse Event Monitoring 
Adverse events will be collected from the time a subject signs the informed consent document 
until the completion of the final study visit (see Table 5, Table 6, Table 7, and Table 8). Adverse 
events and serious AEs (SAEs) are defined in Section 13.1 and Section 13.2, respectively. 


 
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Section 13.4 provides guidance on the monitoring and reporting requirements for AEs. 
Section 13.5 provides guidance on the reporting requirements for SAEs. 
See Section 8.1 for the monitoring and definitions of DLTs. 
8.3.14. 
Tumor Tissue Assessments (Optional) 
Biopsies of tumors in subjects with accessible lesions are taken at baseline and at time points 
specified in Table 5, Table 6, and Table 7. This is optional for subjects.  
The on-treatment biopsy should be taken at the same site as the baseline biopsy if feasible. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Inpatient Treatment 
All subjects participating in the dose-escalation (Part A) portion of the study will stay at a 
medical facility with immediate access to intensive care unit and medical support measures for 
the dosing days of the first 2 cycles of therapy and will be discharged 24 hours after the last dose 
if medically stable. This will apply to all subjects at each dose level in the dose-escalation 
portion of the protocol. If a subject experiences an AE/SAE of concern to the Investigator or a 
DLT in any cycle, the Investigator may choose to administer the next dose or next cycle of doses 
in an inpatient setting, if continued dosing is deemed appropriate for that subject. In the absence 
of any of the events that define a DLT, subjects may receive subsequent cycles after Cycle 2 of 
ALKS 4230 in an outpatient setting. Dosing in subsequent cycles may also be administered to 
subjects as inpatients, if necessary based on the opinion of the Investigator.  
Inpatient treatment and observation are not mandatory for Part B or Part C of the study. 
Subjects should be hospitalized for monitoring (for either Part A, Part B, or Part C) in the event 
of Grade 4 neutropenia (where ANC <100/µL) or Grade 3 or higher febrile neutropenia, as 
outlined in Section 9.7. 
Any subject in any part of the study may be admitted to the hospital for observation and safety 
monitoring at any time during the study if the Investigator believes it to be in the best interest of 
the subject. 
8.4.2. 
Contraception and Pregnancy 
All WOCBP and all men (if their sexual partners are WOCBP) must use at least two methods of 
contraception, at least one of which is considered highly effective, during the study and 90 days 
after the final dose of study drug (for subjects in Part A and Part B) or 4 months after the final 
dose of study drug (for subjects in Part C), if heterosexually active. A woman is considered as a 
WOCBP (fertile) following menarche and until becoming postmenopausal unless permanently 
sterile. Permanent sterilization methods include total hysterectomy and/or bilateral 
salpingectomy and/or bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile 
after puberty unless permanently sterile by bilateral orchiectomy. 


 
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Highly effective methods of contraception include the following: 
• Combined (containing estrogen and progestogen) hormonal contraception associated 
with inhibition of ovulation. Delivery may be oral, intravaginal, or transdermal. 
• Progestogen-only hormonal contraception associated with inhibition of ovulation. 
Delivery may be oral, injectable, or implantable. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or occlusion 
• Bilateral vasectomy (provided that the male has a medical assessment of surgical 
success) 
• True sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk, in line with the preferred and usual lifestyle of the subject) 
All female subjects of childbearing potential will receive a pregnancy test (serum or urine) at 
screening and a negative result must be confirmed before the first dose in each cycle of 
treatment. If a subject becomes pregnant while participating in the study, she will be 
discontinued from study drug immediately. The early termination and safety follow-up visits will 
be scheduled and the pregnancy will be reported to Alkermes. Pregnancies in female partners of 
male subjects should also be reported and will be followed in the same manner. Additional 
follow-up may be required. 
In the event of a pregnancy, a Pregnancy Report Form must be submitted to Alkermes (fax 
number in Section 13.5) within 24 hours of awareness of the pregnancy, irrespective of whether 
an AE has occurred. The pregnancy will be followed until completion or termination. If the 
outcome of the pregnancy meets the criteria for classification as an SAE it should be reported 
following the SAE procedure (see Section 13.5). 
8.4.3. 
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. 
The following treatments are not permitted during the study: 
• Any other investigational treatment 
• Any other systemic antineoplastic therapy including, but not limited to, cytotoxic 
chemotherapy, immunotherapy, targeted agents, hormonal therapy (except luteinizing 
hormone-releasing hormone antagonists or agonists for prostate cancer started at least 
3 months before Cycle 1, Day 1 of ALKS 4230) or monoclonal antibody therapy 
• Radiotherapy, including systemically administered radioisotopes; only palliative 
radiotherapy to a nontarget lesion is allowed at the discretion of the Medical Monitor 


 
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• Hematopoietic growth factors. In Part A, hematopoietic growth factors are prohibited 
during the DLT evaluation period. At all other times in Part A, and at all time in 
Parts B and C, hematopoietic growth factors may be used as clinically indicated. 
• Pharmacologic doses of corticosteroids (greater than 10 mg of prednisone daily, or 
equivalent); topical, ophthalmological, and inhalational corticosteroids are permitted. 
Use of glucocorticoids for the purpose of treating immune-mediated AEs is permitted 
(see Section 9.8) but may result in discontinuation from study based on consultation 
between the Investigator and the Medical Monitor.  
Medroxyprogesterone or megestrol acetate may be given to subjects without breast cancer as an 
appetite stimulant and bisphosphonates or denosumab may be administered to subjects with bone 
metastases if started 60 days before study entry. 
As ALKS 4230 is a protein, there are no anticipated metabolic drug-drug interactions. 
8.4.3.1. 
Premedication 
Antipyretics are required throughout the ALKS 4230 treatment period. To reduce the potential 
for infusion-related fever or chills, premedication with an antipyretic agent (nonsteroidal 
anti-inflammatory drugs and acetaminophen) is required at least 15 minutes prior to ALKS 4230 
administration and should continue for at least 12 hours after the last dose of ALKS 4230 unless 
the Investigator has a rationale to withhold it from the subject. 
8.5. 
Definition of End of the Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed all study periods, including the Safety Follow-up Period and Follow-up Assessments 
or the last scheduled visit as indicated in the Schedule of Assessments (Table 5, Table 6, Table 7, 
and Table 8). 
The end of the study will be the last subject’s last visit (if applicable, the last phone call with the 
Investigator during the Safety Follow-up Period and Follow-up Assessments) as indicated in the 
Schedule of Assessments (Table 5, Table 6, Table 7, and Table 8). 
8.6. 
Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the Institutional Review Board (IRB) or independent 
ethics committee and in accordance with applicable Regulatory Authority mandates is an 
Investigator responsibility. 


 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dose and Administration 
9.1.1. 
ALKS 4230 Dosing and Administration 
ALKS 4230 will be administered IV as a 30-minute infusion through a 0.22 µm in-line filter for 
5 consecutive days, followed by a period off treatment in repeating cycles. During Cycle 1 of 
Parts A and B, the period off treatment will be 9 days, resulting in a cycle length of 14 days 
(2 weeks). Cycle 2 and subsequent cycles will have a period off treatment of 16 days, resulting in 
a cycle length of 21 days (3 weeks) for each cycle. Infusion for each dosing day of each cycle 
should begin within 3 hours (plus or minus) of the infusion start time for Day 1 of that cycle. 
Emergency resuscitation equipment should be available. For the first 2 treatment cycles of 
Part A, ALKS 4230 will be administered inpatient in a medical facility with access to medical 
support measures and to the intensive care unit, if needed. Subjects may be discharged on Day 6 
of each of the first 2 treatment cycles if medically stable. In the absence of DLTs, subsequent 
treatment cycles may be administered on an outpatient basis. For Part B and Part C of the study, 
administration of ALKS 4230 may be done in an outpatient setting  
In Part C, on days where ALKS 4230 is administered in combination with pembrolizumab, 
ALKS 4230 should be administered as an infusion 60 (±30) minutes after the completion of 
pembrolizumab infusion. For Part C, a subject’s ALKS 4230 dose may be reduced by one dose 
level as needed at the discretion of the Investigator. Study drug dose adjustments for all subjects 
are described in Section 9.6. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
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]). 
ALKS 4230 may be infused using peripheral or central venous access per local standards of care 
and the treating Investigator’s judgment. All subjects should have adequate intravenous access to 
allow the immediate management of toxicities. Subjects who do not have adequate peripheral 
venous access should have a central venous access device placed per local standards of care. 
Amount of drug administered is based on subjects’ body weight as measured at Day 1 
(-72 hours) of each cycle. 
Sites must have written procedures in place detailing the healthcare personnel required to be on 
site during subject dosing, the availability of equipment and medications necessary to treat an 
emergency (should it occur) and the process for transferring a subject to a medical facility if 
necessary. 
9.1.2. 
Pembrolizumab Dosing and Administration 
Pembrolizumab is to be administered as an IV infusion over 30 minutes in a dose of 200 mg 
every 3 weeks, for up to 2 years as long as subjects are deriving clinical benefit (ie, objective 
response or SD), in accordance with the prescribing information (Keytruda [pembrolizumab] 
USPI). Subjects will be monitored for at least 1 hour for potential acute reactions to 
pembrolizumab prior to administration of ALKS 4230, as described in Section 9.1.1. 


 
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Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
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]). 
Pembrolizumab is to be obtained from the study sites’ pharmacies, from commercial supplies or 
provided by Sponsor in countries where pembrolizumab is not yet approved. 
 
 
9.2. 
Infusion-Related Reactions 
ALKS 4230 may be associated with infusion-related reactions, including pyrexia, tachycardia, 
and chills with onset 3-6 hours postinfusion. Infusion-related reactions should be treated at the 
discretion of the Investigator. 
 
 
Refer to Section 8.4.3.1 for guidance around medications used for pretreatment. 
Infusion-related reactions associated with the use of pembrolizumab should be managed in 
accordance with the prescribing information for pembrolizumab (Keytruda [pembrolizumab] 
USPI). 
9.3. 
Treatment Adherence 
ALKS 4230 and pembrolizumab will be administered at a medical facility or study center by 
study staff; therefore, compliance is ensured. The clinical research associates will confirm study 
drug was administered and documented in subject’s eCRFs during site visits. 
9.4. 
Method of Assigning Subjects to Treatment 
Randomization is not planned for this open-label study. 
9.5. 
Blinding 
Not applicable for this open-label study. 
9.6. 
Study Drug Dose Adjustments and Stopping Rules 
9.6.1. 
Adverse Events Observed After Dose-Limiting Toxicity Observation Period 
Subjects who are part of the first dose cohort who experience an event that meets the definition 
of a DLT during Cycle 1 or Cycle 2 will be removed from the study. Beyond C2D15, if a subject 
experiences a DLT, a dose reduction of one level (Table 1) may be allowed and treatment 
continued at this reduced dose for all subsequent cycles. If a subject has another DLT at the 
reduced level, another dose reduction may be allowed if, in the Investigator’s opinion, 
benefit-risk assessment warrants continuing ALKS 4230. The Investigator should consult with 
the Medical Monitor for approval to continue to treat at reduced dose. A subject who experiences 
a third DLT after 2 dose reductions should be discontinued from study treatment.  


 
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9.6.2. 
Management of Missed Doses 
 
 
 
 
 
 
 
 
 
 
9.6.3. 
Intrapatient Dose Escalation 
Under the circumstances described below, an individual subject may be permitted to have his/her 
dose escalated (ie, intrapatient dose escalation) upon the mutual agreement of the Investigator 
and the Medical Monitor. Such escalations would increase the subject’s dose to the 
protocol-defined dose level that is one level higher than the subject’s current dose level. For such 
escalation to be considered for a subject, the following criteria must be met: 
• The subject must have tolerated his/her current dose level without experiencing a 
DLT; 
• The higher dose level being considered for the subject must have had its cohort 
enrolled and determined by the SRC to not exceed the MTD and; 
• The Investigator must believe that the dose escalation is in the best interest of the 
subject. 
A subject may have more than one dose escalation. The above criteria must be met for each 
escalation. 
For subjects in Part C Cohorts C1, C2, C3, or C4, intrapatient dose escalation may be considered 
for subjects who had been assigned to the 1 μg/kg/day dose level or the 3 μg/kg/day dose level 
and adequately tolerated combination therapy. Escalation to a dose of 6 μg/kg/day or above may 
be considered after the SRC has determined the dose level to be adequately tolerated. 
9.6.4. 
Cycle Delays 
 
 
 
 
 
 


 
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. 


 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
 
 
 
 
  
 
 
ALKS 4230 is to be administered as an IV infusion as described in Section 9.1.1. 
The Directions for Use will be distributed to the study centers and will provide detailed dose 
preparation, handling, and administration instructions. 
Pembrolizumab is to be administered as an IV infusion over 30 minutes in a dose of 200 mg 
every 3 weeks for as long as subjects are deriving clinical benefit. Pembrolizumab is to be 
administered as described in Section 9.1.2. 
Pembrolizumab is to be obtained from the study sites’ pharmacies, from commercial supplies, or 
provided by Sponsor.
 
 
10.2. 
Packaging and Labeling 
 
 
 
 
10.3. 
Storage 
 
 
 
10.4. 
Handling and Disposal 
Following completion and verification of accountability logs, all vials must be destroyed. Vials 
may be destroyed on site according to GCP and site practice. Alternatively, the Sponsor may 


 
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Protocol ALK4230-A101 v 13.0 
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arrange for destruction with a third-party vendor operating in accordance with GCP and/or Good 
Manufacturing Practice, as applicable. 
10.5. 
Accountability 
The clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug transport records 
during the study and/or at the end of the study. 


 
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Protocol ALK4230-A101 v 13.0 
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11. 
ASSESSMENT OF ANTITUMOR ACTIVITY 
Tumor Assessments 
Antitumor activity will be determined by the measurement of extent of known disease at baseline 
and approximately every 5 to 6 weeks, following each even-numbered treatment cycle. 
Appropriate radiological procedures (computed tomography scanning, magnetic resonance 
imaging, radionuclide imaging) should be conducted to evaluate areas of disease. Superficial 
skin tumors will be measured with calipers and photographed for evaluation. It is requested that 
the initial method of measurement be maintained throughout the course of the study. The 
determination of response will be conducted according to the standard RECIST and iRECIST 
criteria for Parts A, B, and C.  
Refer to the guidelines for RECIST, tumors are assessed as CR, PR, SD, or PD.  
Refer to the guidelines for iRECIST, tumors are assessed as immune CR (iCR), immune PR 
(iPR), immune SD (iSD), or immune PD (iPD).  
For purposes of this study, subjects must meet the definition for SD/iSD for a minimum of 
12 weeks before this assessment can be determined. 
In studies with immunotherapeutic agents, CR, PR, or SD have been shown to occur after an increase 
in tumor burden characterized as PD by RECIST criteria. The conventional response criteria such as 
RECIST may not adequately assess the activity of immunotherapeutic agents. PD evaluated 
radiologically may not mean therapeutic failure, as responses to immune therapies may occur after 
conventional PD. The appearance of measureable antitumor activity may take longer for immune 
therapies than for cytotoxic therapies. With immunotherapeutic agents, there should be allowance for 
clinically insignificant PD, defined as small new lesions in the presence of other responsive lesions, 
which may occur even though the subject is responding to the immunotherapy. Stable disease may 
also represent antitumor activity with iRECIST. Therefore, RECIST and iRECIST will be used to 
ensure a more comprehensive evaluation of tumor response for ALKS 4230. 
The ORR/iORR is the number of subjects exhibiting a CR/iCR or PR or iPR divided by the 
number of subjects evaluable for antitumor activity. Duration of response will also be 
determined. The ORR/iORR will be calculated separately for subjects in the dose-escalation 
portion of the study (Part A), in the dose-expansion part of the study (Part B), and in the 
combination therapy part of the study (Part C). Tumor images will be collected and stored 
centrally. Centralized readings may be used to assess scans beginning in the second stage (N2) of 
Part B cohorts and Part C C5, C6, and C7 cohorts. 


 
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Antitumor activity will be expressed as the following: 
• ORR based on RECIST 
• iORR based on iRECIST 
• DCR per RECIST 
• iDCR per iRECIST 
• DOR per RECIST  
• iDOR per iRECIST 
• PFS per RECIST  
• Immune PFS (iPFS) per iRECIST 
• DRR per RECIST (Part B and Part C5, C6, C7) 
• iDRR per iRECIST (Part B and Part C5, C6, C7) 


 
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Protocol ALK4230-A101 v 13.0 
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12. 
ASSESSMENT OF PHARMACOKINETICS, 
PHARMACODYNAMICS, AND IMMUNOGENICITY 
12.1. 
Pharmacokinetics 
Serum samples for evaluation of ALKS 4230 PK will be obtained from each subject at 
predetermined time points. A validated electrochemiluminescence method using the Meso Scale 
Discovery platform will be used for the quantitation of ALKS 4230 in human serum. 
Noncompartmental PK analysis will be performed to estimate the PK parameters for 
ALKS 4230. 
Remaining serum PK samples obtained during scheduled PK blood draws in Part C, as noted in 
Table 7, may be analyzed for pembrolizumab concentrations at a future date. 
12.2. 
Immunogenicity 
Serum samples for evaluation of anti-ALKS 4230 antibody induction will be obtained from each 
subject at predetermined time points. A validated electrochemiluminescence method using the 
Meso Scale Discovery platform will be used for the detection of antidrug antibodies to 
ALKS 4230 in human serum. The assessment of immune-response induction for each study 
subject will be based on the comparison of the predose and postdose sample results. 
12.3. 
Pharmacodynamics and Biomarkers 
The pharmacodynamic response of various biomarkers will be assessed in blood and serum 
samples collected from all subjects in the study. Additional biomarker analyses may be 
performed on tumor tissue samples, which are optional for study subjects. 
12.3.1. 
Blood-Based Biomarkers 
The pharmacodynamic effect of ALKS 4230 is assessed by measuring circulating CD8+ T cells, 
Tregs, and NK cells in peripheral blood by flow cytometry from each subject at predetermined 
time points.  
In addition, serum samples will be obtained from each subject at predetermined time points. 
Concentration of multiple proinflammatory cytokines including interferon-γ, tumor necrosis 
factor-α, IL-1β, IL-6, and IL-10 will be determined.  
Circulating tumor DNA (ctDNA) will also be measured at predetermined time points. 
12.3.2. 
Tumor Tissue Biomarkers 
12.3.2.1. Tumor Biopsies 
Collection of fresh tumor samples via biopsy is optional during the study. Subjects with 
accessible tumors who are willing to undergo biopsy should provide samples at baseline and 
while on treatment around C2D8. A punch biopsy is preferred for tissue collection from 
melanoma subjects. 
These samples will be analyzed by immunohistochemistry and/or immunofluorescence for 
markers of immune activation. They can also be used for gene expression analysis using method 


 
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such as NanoString. Comparison of on-treatment versus baseline results can be used to 
demonstrate the pharmacologic impact to tumor microenvironment. The analysis of the baseline 
tumor tissues will be used for correlative analysis. Refer to the Laboratory Manual for tumor 
sample handling and processing information. 
12.3.2.2. Archived Tumor 
Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination therapy part 
(Part C) of the study must agree to provide archival tumor tissue biopsy sample(s), if available. 
The archival tumor tissue sample does not have to be obtained prior to enrollment into the study, 
however every effort should be made to submit the archived tissue within 30 days of study 
enrollment. For subjects who have available samples of formalin-fixed, paraffin-embedded 
tumor tissue, 15 unstained glass slides of tissue sections will be provided, to be analyzed. These 
samples will be analyzed by immunohistochemistry and/or immunofluorescence for markers of 
immune activation. They can also be used for gene expression analysis using method such as 
NanoString. Comparison of on-treatment versus baseline results can be used to demonstrate the 
pharmacologic impact to tumor microenvironment. The analysis of the baseline tumor tissues 
will be used for correlative analysis. Refer to the Laboratory Manual for tumor sample handling 
and processing information. 


 
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13. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• Reporting of AEs 
• Collection of vital signs (ie, systolic and diastolic blood pressure, pulse, respiratory 
rate, and body temperature) and weight 
• Clinical laboratory parameters (ie, hematology, chemistry, and urinalysis; see 
Section 8.3.10) 
• ECG parameters (overall assessment; heart rate; RR, PR, QRS, and QTc intervals) 
13.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
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 subject and is considered clinically significant. Thus, an AE 
can be any unintended and unfavorable physical sign, laboratory parameter, or symptom that 
develops or worsens in severity during the course of this study, or significant worsening of the 
disease under study or of any concurrent disease, regardless of relationship to investigational 
treatment. 
Illnesses present before the subject signing the informed consent form (ICF) are considered to be 
preexisting conditions and are documented on the medical history eCRF. Any new or preexisting 
conditions that worsen during the study are entered on the AE eCRF. Disease progression is not 
considered as an AE or SAE. Death resulting from disease progression should not be reported as 
an SAE. 
All out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the Investigator, and may or may not be an AE. An abnormal lab value may be 
considered an AE under the following conditions: 
• It is clinically significant 
• It is an SAE (eg, it requires hospitalization) 
• It requires medical intervention 
• It requires a change or delay in the administration of study drug or permanent 
discontinuation of study drug 
Clinically significant 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 subject will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.2, the pregnancy must be reported to Alkermes 
and additional follow-up may be required. 


 
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Protocol ALK4230-A101 v 13.0 
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13.2. 
Definition of Serious Adverse Event 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• Results in death 
• Is life-threatening. The subject is at immediate risk of death from the reaction as it 
occurs. This does not include 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 and 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 to be SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or subject and may require intervention to prevent one of the 
other outcomes listed above. 
Admission to a hospital or 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 as an 
SAE, but will be reported as an AE. 
Hospitalization due to worsening of behavioral health related issues should be reported as an 
SAE. 
13.3. 
Relationship to Study Drug 
The assessment of study drug relationship 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 
subinvestigator) according to his/her best clinical judgment. The criteria listed in Table 14 should 
be used to guide this assessment. Please note that not all criteria must be present to be indicative 
of a particular drug relationship. All study drugs are considered “test drugs” for the purposes of 
the definitions listed in the table.  
For subjects participating in Part C of the study, AE causality relationships will be attributed to 
both pembrolizumab and ALKS 4230 unless it is explicitly stated otherwise by the Investigator 
(eg, if the AE occurs immediately after pembrolizumab is administered and prior to ALKS 4230 
administration).  


 
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Protocol ALK4230-A101 v 13.0 
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Table 14: 
Adverse Event Causality Guidelines 
Relationship 
Criteria for Assessment 
Definitely related 
There is evidence of exposure to the test drug. AND 
The temporal sequence of the AE onset relative to administration of the test drug 
is reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Rechallenge (if feasible) is positive. 
The AE shows a pattern consistent with previous knowledge of the test drug or 
test drug class. 
Probably related 
There is evidence of exposure to the test drug. AND 
The temporal sequence of the AE onset relative to administration of the test drug 
is reasonable. 
The AE is more likely explained by the test drug than by another cause. 
Dechallenge (if performed) is positive. 
Possibly related 
There is evidence of exposure to the test drug. AND 
The temporal sequence of the AE onset relative to administration of the test drug 
is reasonable. 
The AE could have been due to another equally likely cause. Dechallenge (if 
performed) is positive. 
Probably not 
related 
There is evidence of exposure to the test drug. AND 
There is another more likely cause of the AE. Dechallenge (if performed) is 
negative or ambiguous. Rechallenge (if performed) is negative or ambiguous. 
Definitely not 
related 
The subject did not receive the test drug. OR 
Temporal sequence of the AE onset relative to administration of the test drug is 
not reasonable. 
OR 
There is another obvious cause of the AE. 
13.4. 
Monitoring and Recording of Adverse Events 
Adverse event data collection will begin after a subject signs the ICF and will continue until 
30 days after the final dose of study drug. Any SAE that the Investigator attributes to study drug 
with onset any time after the 30-day period must be reported. Subjects with ongoing AEs will be 
followed by the Investigator until the AE has resolved or returned to the baseline level. 
The Investigator, Medical Monitor, and Sponsor will review the collected data regularly for 
evidence of AEs. All subjects will be assessed routinely for AEs as outlined in the study 
schedule. All AEs observed will be graded using NCI CTCAE version 4.03 or higher. Refer to 
the NCI CTCAE website for descriptions of Grades 1 through 5 for AEs. 
Subjects 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. 


 
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The Investigator will assess all AEs regarding any causal relationship to the study drug (see 
Section 13.3), the intensity (severity) of the event, action taken, and subject outcome. Refer to 
the NCI CTCAE website for descriptions of AE severities. 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
subject is deemed by the Investigator to be lost to follow-up. 
For clinical study safety reporting purposes, the most recent version of the Investigator’s 
Brochure will be used as the reference document to designate event expectedness. For AEs 
associated with pembrolizumab, the prescribing information for pembrolizumab should be used 
as the reference document to designate event expectedness (Keytruda [pembrolizumab] USPI). 
Withdrawal from the study as a result of an AE and any therapeutic measures that are taken shall 
be at the discretion of the Investigator. If a subject withdraws from the study for any reason, any 
ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or until 
the subject is deemed by the Investigator to be lost to follow-up. 
13.5. 
Reporting of Serious Adverse Events 
All SAEs and pregnancies must be reported within 24 hours of discovery, by emailing or 
faxing the report to the following: 
Before 14 Nov 2022 
From 14 Nov 2022 00:00 EST Onwards 
Attention: Syneos Health Safety and 
Pharmacovigilance 
FAX Number: +1 (877) 464-7787 
Email: safetyreporting@syneoshealth.com 
Attention: PPD Safety 
Toll Free Fax: +1 (888) 488 9697 
Direct Dial Fax: +1 (919) 654 3849 
Email: WILSafety@ppd.com 
The written report should be submitted on the SAE form provided for this purpose. The report 
must include the Investigator’s opinion as to whether the event is study drug-related. If this 
relationship is determined to be possibly, probably, or definitely related to study drug, evidence 
to support this assessment must also be provided. 


 
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14. 
STATISTICS 
14.1. 
Determination of Sample Size 
The number of subjects planned to be enrolled in this study is expected to be approximately 
140 to 327. This is based on an assumption of approximately 36 to 54 subjects to be enrolled in 
Part A, 42 to 82 subjects to be enrolled in Part B, and up to 191 subjects to be enrolled in Part C 
(Table 15). 
Table 15: 
Number of Subjects Expected in Each Study Period 
Study Period 
Number of Subjects 
Part A 
N=36-54 (assuming 6 or 7 dose levels) 
Part B  
N=42-82 
Part C new subjects 
N=Up to 191 
Part C rollover subjects 
Not applicable 
Part C safety run-in subjects treated 
at 1 μg/kg/day dose level 
N=3-6 
Total number of subjects exposed to 
ALKS 4230 
N=140-327 
Note: Part C rollover subjects do not contribute the total number of subjects exposed to ALKS 4230.  
In Part A of the study, the number of subjects per dose level is illustrated in Table 1. The number 
of subjects to be enrolled in Part A will depend upon the number of dose escalations, which in 
turn will depend upon the safety profile of ALKS 4230. If 6 or 7 dose levels are enrolled, then 
the number of subjects participating in Part A is expected to be approximately 36 to 54. 
Part B is designed to enroll subjects in each of 2 cohorts based on tumor type and prior therapy. 
The sample size of each cohort was chosen based on methodology described by Simon regarding 
optimal 2-stage designs for Phase 2 studies (Simon 1989). The intention in this study is to enroll 
cohorts that correspond to the first stage of such a design. The assumed alpha is 0.05 and power 
is 90%. Enrollment to these cohorts will follow a PR (unconfirmed) Simon’s two-stage design 
enrollment as outlined below. Response assessments will be based on the RECIST and iRECIST 
guidelines. 
Table 16: 
Simon’s Two-stage Design Enrollment for Part B 
  
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
Expansion Cohort B1: 
Refractory RCC 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Expansion Cohort B2: 
Refractory Melanomaa 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Abbreviations: CR=complete response, PR=partial response, RCC=renal cell carcinoma. 
a No more than 5 ocular melanoma subjects may be enrolled into this cohort. 


 
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Protocol ALK4230-A101 v 13.0 
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The sample size of each cohort was chosen based on methodology described by Simon regarding 
optimal 2-stage designs for Phase 2 studies (Simon 1989). The intention in this study is to enroll 
cohorts that correspond to the first stage of such a design. The assumed alpha is 0.15 and power 
is 85%. Any of the following Part C cohorts may be stopped early if inadequate activity is 
observed: 
• PD-1/L1 unapproved tumor types cohort (zero responses in the first 15 subjects) 
• PD-1/L1 approved tumor types (PD-1/L1 pretreated) cohort (zero responses in the 
first 15 subjects) 
• PD-1/L1 approved tumor types (PD-1/L1 treatment naive) cohort (≤3 objective 
responses in the first 20 subjects) 
The Part C rollover cohort (Cohort 4) is designed to provide access to ALKS 4230 in 
combination with pembrolizumab for subjects initially enrolled into study Part A and Part B. It is 
estimated that between 0 and 54 subjects may potentially enter this cohort. Participation in the 
rollover cohort does not contribute to the overall number of subjects exposed to ALKS 4230. The 
rollover cohort will close to enrollment if the other Part C cohorts have closed early due to 
insufficient antitumor activity. 
Table 17: 
Simon’s Two-stage Design Enrollment for Part C 
  
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
C5: Melanoma 
40% 
55% 
27 
≥12 PR/CR 
26 
53 
C6: NSCLC 
13% 
27% 
18 
≥3 PR/CR 
24 
42 
C7: SCCHN 
15% 
30% 
17 
≥3 PR/CR 
19 
36 
Abbreviations: CR=complete response, NSCLC=non–small-cell lung cancer, PR=partial response, SCCHN=squamous 
cell carcinoma of the head and neck. 
14.2. 
General Statistical Methodology 
The statistical analysis methods are described below. Additional details will be provided in the 
Statistical Analysis Plan (SAP) to be finalized before database lock. 
In general, summary statistics (n, mean, standard deviation, median, minimum, and maximum 
values for continuous variables and number and percentage of subjects in each category for 
categorical variables) will be provided for evaluated variables. All individual subject level data 
will be presented as data listings. 
No inferential testing procedures are planned in this study. 
Data will be summarized for Part A, Part B, and Part C separately. In addition, data regarding 
antitumor activity for subjects in Part A who are treated at the RP2D dose may be summarized 
with subjects from Part B. The cumulative tumor response and AE data will be summarized for 
subjects who enter into the Extension Phase; additional details will be specified in the SAP. 
Baseline is defined as the last value prior to the first dose of study treatment administration for 
each part separately.  


 
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14.3. 
Study Populations 
14.3.1. 
Safety Population 
In Part A and Part B, the safety population will include all subjects who received ALKS 4230. In 
Part C, all subjects exposed to ALKS 4230 or pembrolizumab will be included in the safety 
population. This population will be used for all safety analyses. 
14.3.2. 
Pharmacokinetic and Pharmacodynamic Population 
The PK population will consist of all subjects who received at least 1 dose of ALKS 4230 and 
have at least 1 measurable serum concentration of ALKS 4230 at any scheduled PK time point. 
The PD population will consist of all subjects who received at least 1 dose of ALKS 4230 and 
have at least one available postbaseline pharmacodynamics measurement. 
14.3.3. 
Antitumor Evaluable Population  
The antitumor evaluable population will consist of subjects who complete 2 cycles of therapy 
and have at least one follow-up scan.  
14.4. 
Statistical Analysis 
14.4.1. 
Subject Disposition, Baseline Demographics, and Treatment Characteristics 
14.4.1.1. Subject Disposition 
The number of subjects in the safety population from each study part and the reasons for 
discontinuation will be summarized. In addition, subjects’ status with regard to study treatment 
and follow-up will also be summarized in the Final Study Report. 
14.4.1.2. Demographics and Baseline Characteristics 
Subject disease and baseline characteristics will be summarized using frequency distribution or 
descriptive statistics as appropriate. 
14.4.1.3. Study Treatment 
The ALKS 4230 administration profile will be summarized with respect to number of cycles 
taken, the dose intensity, dose modifications, and reasons for deviations from the planned 
regimen. 
14.4.2. 
Antitumor Activity Analyses 
Antitumor activity analyses will be based on the antitumor population. 
14.4.2.1. Overall Response Rate 
The evaluation of ORR will be based on Investigator review of the radiographic or photographic 
images, as defined according to RECIST 1.1. In addition, central review may be assessed for 
select cohorts (N2 of Part B cohorts and N2 of Part C C5, C6, and C7 cohorts). Overall response 


 
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rate is defined as the proportion of subjects with objective evidence of CR or PR among the 
number of subjects evaluable for antitumor activity. 
At the analysis stage, the best ORR will be assigned for each subject as the best response 
recorded after initiation of study treatment, taking into account any requirement for confirmation. 
If applicable, responses recorded after disease progression or initiation of new anticancer 
treatment will be excluded. 
The ORR will be calculated separately for those subjects in the dose-escalation portion of the 
study (Part A), in the dose-expansion portion of the study (Part B), and in the combination 
therapy part of the study (Part C). 
Summarization of ORR will be presented by frequency, percentage, and 95% confidence interval 
(CI). The CI will be obtained using an exact approach given the small sample size. 
Sum of the Diameters of all lesions reported at each visit will be graphed by spider plot 
(% change over time) and waterfall plot (best % change). The swimmer plot will be used to 
display the characteristics of the responses in subjects. 
14.4.2.2. Immune Overall Response Rate 
The Investigator is asked to consult Seymour et al 2017 for full description of iRECIST. iRECIST 
is based on RECIST 1.1. Responses assigned using iRECIST have a prefix of “i” (ie, immune) to 
differentiate them from responses assigned using RECIST 1.1. The principles used to establish 
objective tumor response are largely unchanged from RECIST 1.1, but the major change for 
iRECIST is the concept of resetting the bar if RECIST 1.1 progression is followed at the next 
assessment by tumor shrinkage.  
iRECIST defines iUPD (immune unconfirmed progressive disease) on the basis of RECIST 1.1 
principles. If the criteria for iUPD have never been met, principles follow RECIST 1.1. 
However, if the criteria for iUPD have been met, the next timepoint response could be iUPD, 
iSD, iPR, or iCR, or iCPD (immune confirmed progressive disease). 
For iRECIST, the best overall response (iBOR) is the best timepoint response recorded from the 
start of the study treatment until the end of the study treatment, taking into account any 
requirement for confirmation. Immune overall response rate will be based on iBOR.  
The iBOR will be calculated separately for those subjects in the dose-escalation portion of the 
study (Part A), in the dose-expansion portion of the study (Part B), and in the combination 
therapy part of the study (Part C). A spider plot, waterfall plot, and swimmer plot will be used to 
display the characteristics of the responses in subjects. 
14.4.2.3. Disease Control Rate 
Disease control rate is defined as the proportion of subjects with objective evidence of CR, PR, 
or SD at Cycle 4 or later.  
The DCR will be calculated separately for those subjects in the dose-escalation portion of the 
study (Part A), in the dose-expansion portion of the study (Part B), and in the combination 
therapy part of the study (Part C). 


 
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Summarization of DCR will be presented by frequency, percentage, and 95% CI. The CI will be 
obtained using an exact approach given the small sample size. 
14.4.2.4. Immune Disease Control Rate 
Immune disease control rate is defined as the proportion of subjects with objective evidence of 
iCR, iPR, or iSD at Cycle 4 or later.  
The iDCR will be calculated separately for those subjects in the dose-escalation portion of the 
study (Part A), in the dose-expansion portion of the study (Part B), and in the combination 
therapy part of the study (Part C). 
Summarization of iDCR will be presented by frequency, percentage, and 95% CI. The CI will be 
obtained using an exact approach given the small sample size. 
14.4.2.5. Duration of Response (Part B and Part C) 
Duration of response, defined as the time from the first documentation of response (CR or PR) to 
the first documentation of objective tumor progression or death due to any cause. Subjects who 
are alive and progression free as of the analysis cut-off date will be censored at their last 
evaluable tumor response assessment before initiation of any new anticancer treatment. Subjects 
with two or more consecutive missing response assessments prior to death or a visit with 
documented progression will be censored at the last date of tumor assessment when the subject 
was documented to be progression free. Subjects who never achieve CR or PR prior to starting 
any new anticancer treatment at a lesion site will be excluded from the analysis. 
The rate of response will be calculated for RECIST responders. 
For Part B, the DOR will be calculated as follows (in weeks): 
(date of PD/death in Part B – date of first response (CR or PR) in Part B + 1)/7 
For Part C, the DOR will be calculated as follows (in weeks): 
(date of PD/death in Part C – date of first response (CR or PR) in Part C + 1)/7 
The distribution of DOR will be estimated for Part B and Part C using Kaplan-Meier 
methodology. The median point estimate DOR will be provided along with the two-sided 95% 
CIs based on the antitumor evaluable population with subjects who experienced CR or PR. 
Kaplan-Meier curves will be provided. 
14.4.2.6. Immune Duration of Response (Part B and Part C) 
Immune duration of response, defined as the time from the first documentation of response (iCR 
or iPR) to the first documentation of objective tumor progression or death due to any cause. 
Subjects who are alive and progression free as of the analysis cut-off date will be censored at 
their last evaluable tumor response assessment before initiation of any new anticancer treatment. 
Subjects with two or more consecutive missing response assessments prior to death or a visit 
with documented progression will be censored at the last date of tumor assessment when the 
subject was documented to be progression free. Subjects who never achieve iCR or iPR prior to 
starting any new anticancer treatment at a lesion site will be excluded from the analysis. 


 
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The rate of response will be calculated for iRECIST responders. 
For Part B, the iDOR will be calculated as follows (in weeks): 
(date of iPD/death in Part B – date of first response (iCR or iPR) in Part B + 1)/7 
For Part C, the iDOR will be calculated as follows (in weeks): 
(date of iPD/death in Part C – date of first response (iCR or iPR) in Part C + 1)/7 
The distribution of iDOR will be estimated for Part B and Part C using Kaplan-Meier 
methodology. The median point estimate iDOR will be provided along with the two-sided 95% 
CIs based on the antitumor evaluable population with subjects who experienced iCR or iPR. 
Kaplan-Meier curves will be provided. 
14.4.2.7. Durable Response Rate (Part B and Part C) 
Durable response rate is defined as the percentage of subjects with an objective response 
(complete or partial response per RECIST1.1) lasting continuously for 6 months and starting any 
time within 12 months of initiating the study drug. The DRR will be summarized by each tumor 
type. Summary of DRR will be presented by frequency, percentage, and 95% CI. The CI will be 
obtained using an exact approach given the small sample size.  
Immune durable response rate (iDRR) is defined as the percentage of subjects with an objective 
response (complete or partial response per iRECIST) lasting continuously for 6 months and 
starting any time within 12 months of initiating the study drug. The iDRR will be summarized by 
each tumor type. Summary of iDRR will be presented by frequency, percentage, and 95% CI. 
The CI will be obtained using an exact approach given the small sample size. 
14.4.2.8. Progression-free Survival (Part B and Part C) 
Progression-free survival, defined as the time from the first dose of ALKS 4230 to the first 
documentation of objective tumor progression or death due to any cause. Subjects who do not 
have disease progression or have not died will be censored at the last known time that the subject 
was progression free. If a subject begins a new anticancer treatment (either systemic or local) 
prior to documented progression or death, or a subject is removed from the study due to 
undocumented clinical disease progression, then the subject will be censored at the last 
assessment where the subject was documented as progression free prior to the intervention. 
Subjects with two or more consecutive missing response assessments prior to a visit with 
documented progression (or death) will be censored at the last date of tumor assessment when 
the subject was documented to be progression free.  
For Part B, the PFS will be calculated as follows (in weeks): 
(date of PD/death in Part B – first dose date in Part B + 1)/7 
For Part C, the PFS will be calculated as follows (in weeks): 
(date of PD/death in Part C– first dose date in Part C + 1)/7 
The survival distribution of PFS will be estimated using Kaplan-Meier methodology. The 
median PFS will be provided along with the two-sided 95% CIs based on the antitumor 
evaluable population. In addition, Kaplan-Meier curves will be provided. The 6-month and 
one-year PFS rate will be estimated using the Kaplan-Meier estimate. 


 
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14.4.2.9. Immune Progression-free Survival (Part B and Part C) 
Immune progression-free survival, defined as the time from the first dose to the first 
documentation of objective tumor progression or death due to any cause. Subjects who do not 
have disease progression or have not died will be censored at the last known time that the subject 
was progression free. If a subject begins a new anticancer treatment (either systemic or local) 
prior to documented progression or death, or a subject is removed from the study due to 
undocumented clinical disease progression, then the subject will be censored at the last 
assessment where the subject was documented as progression free prior to the intervention. 
Subjects with two or more consecutive missing response assessments prior to a visit with 
documented progression (or death) will be censored at the last date of tumor assessment when 
the subject was documented to be progression free.  
For Part B, the iPFS will be calculated as follows (in weeks): 
(date of iPD/death in Part B – first dose date in Part B + 1)/7 
For Part C, the PFS will be calculated as follows (in weeks): 
(date of iPD/death in Part C– first dose date in Part C + 1)/7 
The survival distribution of iPFS will be estimated using Kaplan-Meier methodology. The 
median iPFS will be provided along with the two-sided 95% CIs based on the antitumor 
evaluable population. In addition, Kaplan-Meier curves will be provided. The 6-month and 
one-year iPFS rate will be estimated using the Kaplan-Meier estimate. 
Details of the analysis will be specified in the SAP. 
14.4.3. 
Pharmacokinetic Analyses 
Individual serum concentrations and concentration-time data will be presented and summarized 
both graphically and in tabular form using descriptive statistics. Pharmacokinetic parameters will 
be summarized using descriptive statistics. A subject listing of individual PK concentration will 
be provided. Concentration data will be summarized according to nominal (protocol-specified) 
sampling times. Pharmacokinetic parameters will be calculated by noncompartmental analysis 
method using Phoenix WinNonlin Professional (version 6.1 or later, Pharsight Corporation); 
actual elapsed time from dosing will be used to estimate individual serum PK parameters. Dose 
proportionality and additional PK analyses may be performed, as appropriate. 
Details of the analysis will be specified in the SAP. 
14.4.4. 
Pharmacodynamic Analyses 
Pharmacodynamic data will be summarized descriptively. Where possible, the relationship 
between serum PK parameters or concentration of ALKS 4230 and pharmacodynamic responses 
will be evaluated by correlation analysis or visual inspections. The detailed analytical method 
will be specified in the SAP. 
14.4.5. 
Immunogenicity Analysis 
The presence of anti-ALKS 4230 antibodies will be determined and the data will be summarized 
by cohort/dose level. 


 
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14.4.6. 
Tissue Biomarker Analysis 
The baseline values, post-treatment values, and the changes in density of TILs, ratio of cytotoxic 
TILs, immunosuppressive TILs, and density of signals of immune-cell–mediated killing will be 
summarized. 
The correlation between antitumor efficacy endpoints (best overall response, progression free 
survival) and baseline status (or values) for endpoints derived from tumor tissues will be 
estimated. The efficacy endpoints will be summarized separately based on baseline status, or low 
and high values.  
The correlation between antitumor efficacy endpoints (best overall response, progression free 
survival) and the change from baseline in post-treatment for endpoints derived from tumor 
tissues will be estimated.  
14.4.7. 
Safety Analyses 
The safety population will be used for safety analysis. 
Treatment-emergent AEs are defined as AEs that are newly occurring or worsening from the 
time of the first dose of study drug. Reported AE terms will be coded using Medical Dictionary 
for Regulatory Activities terminology, and the severity of the toxicities will be graded according 
to the NCI CTCAE (version 4.03 or higher) where applicable. 
The number and percentage of subjects with treatment-emergent AEs will be summarized by 
dosing group and overall, by severity, by toxicity/severity grade, and by relationship to study 
drug. Serious AEs, Grade 3 or 4 AEs, and AEs contributing to discontinuation from the study 
will be summarized. 
Observed values and change from baseline in vital signs, ECG, and laboratory parameters will be 
summarized by dosing group. Shift table and number (percentage) of subjects with potentially 
clinically significant values at any postbaseline visit will also be summarized as appropriate. In 
addition, hematological and chemistry laboratory parameters will be graded according to the NCI 
CTCAE (version 4.03 or higher) where applicable. The worst severity grade, time to maximum 
Grade 3 or 4 value, and time to resolution (return to baseline grade or below) will be 
summarized. 
Concomitant medications will be coded using the World Health Organization Anatomical 
Therapeutic Chemical drug classification system. The number and percentage of subjects using 
concomitant medications will be summarized. 
14.5. 
Interim Analysis 
No formal interim analysis is planned with respect to stopping the study early or for lack of 
antitumor activity purposes. An interim data cut will be conducted to support abstract 
submissions, conference presentations, and/or manuscript(s). 
A review of safety data will be done at the conclusion of Part A to inform the dose selection for 
Part B. An additional review of safety data will be done after the run-in phases (after 3 subjects 
are treated at the 1 μg/kg/day dose of ALKS 4230 and again after 6 subjects are treated at the 
3 μg/kg/day dose of ALKS 4230) of Part C to assess the safety of ALKS 4230 in combination 
with pembrolizumab. 


 
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Responses in each N1 stage will be assessed to determine whether progression to the N2 stage is 
warranted, based on criteria defined in Section 14.1. 
14.6. 
Independent Data Monitoring Committee 
An IDMC will be established by the Sponsor to review accumulating safety and efficacy data at 
regular intervals and monitor overall study conduct beginning in the second stage (N2) of Part B 
cohorts and Part C C5, C6, and C7 cohorts. Members will include experts in oncology and 
biostatistics, who are not participating in this study and do not have affiliation with the 
investigators or the Sponsor. The IDMC’s specific duties, as well as statistical monitoring 
guidelines and procedures, will be fully described in an IDMC charter. 


 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Monitoring of the study center (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by an Alkermes designee. 
15.2. 
Audits and Inspections 
By signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of Alkermes, a Regulatory 
Authority, and/or an IRB may visit the site to perform audits or inspections, including the drug 
storage area, study drug stocks, drug accountability records, subject charts and source 
documents, and other records relative to study conduct. The purpose of an Alkermes audit or 
inspection is to systematically and independently examine all study-related activities and 
documents (eg, laboratory reports, computed tomography scans/magnetic resonance imaging 
scans, workbooks, subjects’ medical records) to determine whether these activities were 
conducted, and data recorded, analyzed, and accurately reported according to the protocol, GCP 
guidelines of ICH, and any applicable regulatory requirements. 
The Investigator should contact the Alkermes Study Team immediately if contacted by a 
regulatory agency regarding an inspection. 
15.3. 
Institutional Review Board/Independent Ethics Committee 
The Investigator must obtain IRB approval for the investigation. Initial IRB approval as well as 
all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection. 


 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness, and compliance, the study center should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 15.2 for details regarding the audit process. 
16.1. 
Case Report Forms 
This study will use eCRFs. 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 before review by the Alkermes monitor or designated representative. Each staff 
member will obtain a unique user name and password to access the electronic data capture 
database. 
The Alkermes designated representative will review all source records and compare them to the 
data collected on the eCRF for processing of source data review and source data verification 
according to specifications noted in the clinical monitoring plan. The treating Investigator is 
expected to review and sign off on laboratory reports for clinical significance. 
16.2. 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to Alkermes that he or she will maintain in 
confidence information furnished to him or her by Alkermes and will divulge such information 
to his or her respective IRB under an appropriate understanding of confidentiality with such 
board. All data will be considered the sole property of Alkermes. Please refer to the Clinical 
Study Agreement (CSA) for details. 


 
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17. 
ETHICAL CONSIDERATIONS 
17.1. 
Ethics Review 
The clinical site’s IRB must meet all relevant regulatory requirements. The study protocol and 
ICF will be reviewed by the IRB before enrolling subjects into the study; written approval from 
the committee must be received by Alkermes before drug will be released to the Investigator. 
The protocol must be re-approved by the IRB upon receipt of amendments and annually, as local 
regulatory requirements require. 
The Investigator is responsible for submitting all protocol changes and SAE reports to the IRB 
according to local procedures. At a minimum, all SAEs requiring an investigational new drug 
safety report must be immediately reported. 
All relevant correspondence from the IRB will be forwarded by the respective study center to the 
Sponsor in a timely fashion. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the ICH Guideline E6, and all 
applicable local regulatory requirements. GCP is an international ethical and scientific quality 
standard used for designing, conducting, recording, and reporting studies involving the 
participation of human subjects. Alkermes is committed to complying with this standard to 
provide assurance that the rights, safety, and well-being of study subjects will be protected, 
consistent with the principles having their origin in the Declaration of Helsinki. 
17.3. 
Written Informed Consent 
The Investigator (or authorized designee) at each center will ensure that the subject (or the 
subject’s legal representative) is given full and adequate oral and written information about the 
nature, purpose, and potential and possible risks and benefits of the study. Each prospective 
subject will receive an IRB-approved ICF that summarizes the pertinent study information and 
will be given ample time to read the form and ask questions about the study. All information is to 
be provided in a language understandable to the subject and must not include any language that 
waives the subject’s legal rights. Prospective subjects must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the subject chooses to 
participate, he or she must sign and date the ICF before any study-specific procedures are 
conducted. 
All subjects will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, the IRB, the contract research organization 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 monitor may inspect their medical records to verify the accuracy and completeness 
of the study records and results. 
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, and then signed by all applicable study 
participants. 


 
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The time that informed consent is obtained must be documented. The Investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the subject. 


 
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18. 
DATA HANDLING AND RECORD-KEEPING 
An overview of study data handling and record-keeping procedures and restrictions is provided 
in the subsequent sections; please refer to the CSA for further details. 
18.1. 
Data Capture 
As stated in Section 16.1, 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 electronic 
data capture system maintains a full audit trail. 
A copy of all images (computed tomography scan, magnetic resonance imaging scan, or 
photographs) will be stored with the source documents at the study site. 
A copy of all laboratory reports will remain with the source documents at the study center. All 
out-of-range laboratory values will be deemed as clinically significant or not clinically 
significant by the Investigator. Clinically significant values will be considered AEs and recorded 
as such on the eCRFs. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities. Concomitant 
medications will be categorized using the World Health Organization Anatomical Therapeutic 
Chemical classification system. 
18.2. 
Inspection of Records 
Alkermes 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, 
subject charts and source documents, and other records relative to study conduct. 
18.3. 
Retention of Records 
Retention and storage of essential clinical study documents (eg, worksheets, drug accountability 
forms, and other administrative documentation) 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 until at least 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. 
Subjects’ 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. 


 
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18.4. 
Use of Information and Publication Policy 
Data generated in this study are proprietary information that is the sole property of Alkermes. 
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. 


 
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19. 
REFERENCES 
Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune 
system. Nat Rev Immunol. 2012;12(3):180-190. doi: 10.1038/nri3156. 
Diab A. Pivot-02: Preliminary safety, efficacy and biomarker results from the Phase 1/2 study of 
CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic 
solid tumors. Journal for ImmunoTherapy of Cancer. 2017. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi: 
10.1016/j.ejca.2008.10.026. 
Gong JH, Maki G, Klingemann HG. Characterization of a human cell line (NK-92) with 
phenotypical and functional characteristics of activated natural killer cells. Leukemia. 
1994;8(4):652-658. 
Huh D, Leslie DC, Matthews BD, et al. A human disease model of drug toxicity-induced 
pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med. 2012;4(159). doi: 
10.1126/scitranslmed.3004249. 
International Council for Harmonisation. ICH Guidance: S9 Nonclinical Evaluation for 
Anticancer Pharmaceuticals. 2010. 
Intron A US Prescribing Information. Whitehouse Station, NJ: Schering Corporation/Merck & 
Co, Inc. 
Keytruda [pembrolizumab] US Prescribing Information. Whitehouse, NJ: Merck & Co, Inc. 
Krieg C, Letourneau S, Pantaleo G, Boyman O. Improved IL-2 immunotherapy by selective 
stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci U S A. 
2010;107(26):11906-11911. doi: 10.1073/pnas.1002569107. 
Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 
2007;12(5):601-609. doi: 10.1634/theoncologist.12-5-601. 
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Management of 
Immunotherapy-Related Toxicities. Version 1.2020. December 16, 2019. Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
Opdivo [nivolumab] US Prescribing Information. Princeton, NJ: Bristol-Myers Squibb. 
Parish CR. Cancer immunotherapy: the past, the present and the future. Immunol Cell Biol. 
2003;81(2):106-113. doi: 10.1046/j.0818-9641.2003.01151.x. 
Proleukin US Prescribing Information. San Diego, CA: Prometheus Therapeutics & Diagnostics. 


 
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Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-152. doi: 10.1016/S1470-
2045(17)30074-8. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. doi: 
10.3322/caac.21254. 
Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth 
Factor Rev. 2014;25(4):377-390. doi: 10.1016/j.cytogfr.2014.07.018. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. 
Starkebaum G, Loughran TP, Jr., Waters CA, Ruscetti FW. Establishment of an IL-2 
independent, human T-cell line possessing only the p70 IL-2 receptor. Int J Cancer. 
1991;49(2):246-253. doi: 10.1002/ijc.2910490218. 
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. 
CA Cancer J Clin. 2015;65(2):87-108. doi: 10.3322/caac.21262. 
Wrangle JM, Velcheti V, Patel MR, et al. ALT-803, an IL-15 superagonist, in combination with 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 1 of 73 
Document Type: 
Template 
Document ID: 
03.007A.03 
Document Type: 
02 MAY 2016  
Effective Date:    30 MAY 2016  
 
Sponsor Name: 
Alkermes, Inc. 
Protocol Number  
and Title: 
 
ALK4230-A101 
A Phase 1/2 Study of ALKS 4230 Administered Intravenously 
as Monotherapy and in Combination With Pembrolizumab in 
Subjects With Advanced Solid Tumors- ARTISTRY-1 
Protocol Version  
and Date: 
Version 13.0: 08 Sep 2022 
Version 12.2 (Amendment 11.2 – EU only): 18 May 20 
Version 12.1 (Amendment 11.1- AUS only): 28 Feb 20 
Version 12.0 (Amendment 11.0 – US, Canada and Korea): 10 
Feb 20 
Version 11.2 (Amendment 10.2- AUS only): 14 Oct 2019 
Version 11.1 (Amendment 10.1- CAN only): 17 Jun 2019  
Version 11.0 (Amendment 10- US, EU and Korea): 01 May 
2019 
Version 10.0 (Amendment 9): 09 Aug 2018 
Version 9.0 (Amendment 8): 22 May 2018 
Version 8.0 (Amendment 7): 12 Jan 2018 
Version 7.0 (Amendment 6): 20 Dec2017 
Version 6.0 (Amendment 5): 06 Oct 2017 
Version 5.0 (Amendment 4): 08 Jun 2017 
Version 4.0 (Amendment 3): 11 Oct 2016 
Version 3.0 (Amendment 2): 10 Feb 2016 
Version 2.0 (Amendment 1): 13 Oct 2015 
Original Protocol: 07 Jul 2015  
ClinicalTrials.gov 
Identifier: 
 
NCT02799095 
Syneos Health 
Project Code: 
1006212 
Author(s): 
 Supporting Biostatistician (V3.0)    
 
 PhD, Sr. Principal Biostatistician (V2.0) 
 Senior Biostatistician (V1.7) 
SAP Version: 
 V3.0 
SAP Version 
Date:  
03 Mar 2023 


Statistical Analysis Plan 
Alkermes Protocol # ALK4230-A101 
Version V3.0 
 
Syneos Health # 1006212 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 2 of 73 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Alkermes, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from 
an official of Alkermes, Inc. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, Syneos 
Health should be notified promptly. 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Alkermes Protocol # ALK4230-A101 
Version V3.0 
 
Syneos Health # 1006212 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 3 of 73 
Revision History 
 
Version 
# 
Date 
(dd-mmm-
yyyy) 
Document 
Owner 
Revision Summary 
V.0.1 
30-Nov-2016 
Initial Release Version 
V.0.2 
07-Feb-2017 
2nd Draft SAP 
V.1.0 
25-Apr-2017 
Final SAP 
V1.1 
07-Sep-2017 
Add PK/PD parameter derivation 
sections 
V1.2 
25-Sep-2017 
Address Alkermes comments and send 
2nd draft revision SAP 
V1.3 
14-Dec-2018 
Update SAP and shells per protocol 
amendment #9 
V1.4 
19-Nov-2019 
Update SAP and shells per protocol 
amendment #10 
V1.5 
15-Jan-2020 
Update SAP and shells per protocol 
amendment #11. Shared with Alkermes 
on 04 Feb 2020. 
V1.6 
22-Oct-2020 
Update SAP and shells after iRECIST 
implementation in the database and 
request of additional specific outputs 
for publications, according to Protocol 
V12.2 


Statistical Analysis Plan 
Alkermes Protocol # ALK4230-A101 
Version V3.0 
 
Syneos Health # 1006212 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 4 of 73 
Version 
# 
Date 
(dd-mmm-
yyyy) 
Document 
Owner 
Revision Summary 
V1.7  
08-Jan-2021 
Update SAP following Sponsor’s 
comments. PK, PD and ADA part 
removed on Sponsor’s request. 
V1.8 
12-Feb-2021 
Update SAP per Sponsor’s review 
comments and discussions on V1.7 and 
updated shells from V1.6 accordingly 
V1.9 
02-Mar-2021 
Update SAP per Sponsor’s review 
comments on V1.8 and updated 
signature pages 
V1.10 
12-May-2021 
Update SAP per Sponsor’s review 
comments on V1.9 
V1.11 
31-May-2021 
Update SAP per Sponsor’s review 
comments on V1.10 
• 
Added clarification about PK and 
PD related responsibilities.  
• 
Removed scheduled event and 
referred to protocol related 
sections. 
• 
Added deviation from protocol   
V2.0 
11-Jun-2021 
Same as V1.11 but signed version 


Statistical Analysis Plan 
Alkermes Protocol # ALK4230-A101 
Version V3.0 
 
Syneos Health # 1006212 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
Syneos Health 
Page 5 of 73 
Version 
# 
Date 
(dd-mmm-
yyyy) 
Document 
Owner 
Revision Summary 
V3.0 
03-Mar-2023 
Update SAP and shells per protocol 
amendment #13. 
• 
Added extension phase. 
• 
Updated exposure analysis of 
ALKS 4230. 
• 
Removed exposure analysis of 
Pembrolizumab. 
• 
Changed laboratory data unit 
used in summary table from 
conventional unit to SI unit. 
Removed all iRECIST listings.  


Statistical Analysis Plan 
Alkermes Protocol # ALK4230-A101 
Version V3.0 
 
Syneos Health # 1006212 
 
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I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
Syneos Health 
 
 
 
  
Supporting Biostatistician 
 
 
Date (dd-mmm-yyyy) 
Lead and Senior Reviewing Biostatistician 
, PhD 
Senior Principal Biostatistician 
 
 
Date (dd-mmm-yyyy) 
 
 
 


Statistical Analysis Plan 
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TABLE OF CONTENTS 
Contents 
1. 
GLOSSARY OF ABBREVIATIONS ............................................................... 11 
2. 
PURPOSE ...................................................................................................... 16 
2.1. 
Responsibilities ................................................................................................................. 16 
2.2. 
Timings of Analyses .......................................................................................................... 16 
3. 
STUDY DESIGN ............................................................................................ 17 
3.1. 
Primary Objective .............................................................................................................. 17 
3.2. 
Secondary Objectives ....................................................................................................... 17 
3.3. 
Exploratory Objectives ...................................................................................................... 17 
3.4. 
Brief Description ................................................................................................................ 18 
3.5. 
Subject Selection ............................................................................................................... 24 
3.5.1. 
Inclusion Criteria ......................................................................................................... 24 
3.5.2. 
Exclusion Criteria ........................................................................................................ 28 
3.6. 
Determination of Sample Size .......................................................................................... 30 
3.7. 
Treatment Assignment & Blinding ................................................................................... 31 
3.8. 
Administration of Study Drug ........................................................................................... 32 
3.8.1. 
ALKS 4230 Dosing and Administration ....................................................................... 32 
3.8.2. 
Pembrolizumab Dosing and Administration ................................................................ 32 
3.9. 
Study Procedures and Flowchart ..................................................................................... 34 
4. 
ENDPOINTS .................................................................................................. 35 
4.1. 
Primary endpoint ............................................................................................................... 35 
4.2. 
Secondary Endpoints ........................................................................................................ 35 
4.3. 
Exploratory Endpoints ...................................................................................................... 35 
4.4. 
Antitumor Activity Endpoints ........................................................................................... 36 


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4.5. 
Safety Endpoints ................................................................................................................ 36 
4.6. 
Tissue Biomarkers enDPOINTS ....................................................................................... 36 
5. 
ANALYSIS SETS ........................................................................................... 38 
5.1. 
Safety Population ............................................................................................................... 38 
5.2. 
Antitumor Evaluable Population ...................................................................................... 38 
5.3. 
Protocol Deviations ........................................................................................................... 38 
5.4. 
Pharmacodynamic Population ......................................................................................... 38 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 39 
6.1. 
General Methods ................................................................................................................ 39 
6.2. 
Key Definitions ................................................................................................................... 40 
6.2.1. 
Cycle 1 Day 1 .............................................................................................................. 40 
6.2.2. 
Enrollment ................................................................................................................... 40 
6.2.3. 
Treatment Period ........................................................................................................ 40 
6.2.4. 
Study Day .................................................................................................................... 40 
6.2.5. 
Cycle Start/End Day .................................................................................................... 40 
6.2.6. 
Cut-Off Date of Final Analysis ..................................................................................... 41 
6.2.7. 
Baseline and Change from Baseline ........................................................................... 41 
6.3. 
Missing Data ....................................................................................................................... 42 
6.3.1. 
Imputation of Missing Adverse Events/Prior or Concomitant Medications ................. 42 
6.4. 
Visit Windows ..................................................................................................................... 44 
6.5. 
Pooling of Centers ............................................................................................................. 44 
6.6. 
Subgroups .......................................................................................................................... 44 
6.7. 
Handling Pharmacodynamics Data Below the Lower Limit of Quantification or 
missing............................................................................................................................................. 44 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION................................................................................................. 46 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 46 
7.2. 
Demographic and Other Baseline Characteristics ......................................................... 47 
7.3. 
Cancer Disease History ..................................................................................................... 47 


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7.4. 
Medical History .................................................................................................................. 47 
7.5. 
Prior Surgeries and Therapies ......................................................................................... 47 
7.6. 
Prior and Concomitant Medication .................................................................................. 48 
8. 
EFFICACY ..................................................................................................... 49 
8.1. 
Overall Response Rate (ORR) .......................................................................................... 50 
8.2. 
Disease Control Rate (DCR) ............................................................................................. 51 
8.3. 
Duration of Response (DOR) (Part B AND Part C) ......................................................... 51 
8.4. 
Durable Response Rate (Part B and Part C) ................................................................... 52 
8.5. 
Progression-free Survival (PFS) (Part B and Part C Cohorts C5, C6, C7 only) ........... 52 
8.6. 
Time to Response (TTR) (Part B AND Part C) ................................................................. 54 
9. 
SAFETY ANALYSES ..................................................................................... 55 
9.1. 
Extent of Exposure ............................................................................................................ 55 
9.2. 
Dose-Limiting Toxicities ................................................................................................... 56 
9.3. 
Adverse Events .................................................................................................................. 57 
9.4. 
Laboratory Evaluations ..................................................................................................... 59 
9.5. 
Vital Signs ........................................................................................................................... 61 
9.6. 
ECG ..................................................................................................................................... 62 
9.7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ........................... 62 
9.8. 
Physical Examination ........................................................................................................ 62 
10. INTERIM ANALYSES .................................................................................... 63 
11. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................. 64 
12. REFERENCE LIST ........................................................................................ 65 
13. PROGRAMMING CONSIDERATIONS .......................................................... 66 


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13.1. 
General Considerations .................................................................................................... 66 
13.2. 
Table, Listing, and Figure Format .................................................................................... 66 
13.2.1. 
General ........................................................................................................................ 66 
13.2.2. 
Headers ....................................................................................................................... 67 
13.2.3. 
Display Titles ............................................................................................................... 67 
13.2.4. 
Column Headers ......................................................................................................... 67 
13.2.5. 
Body of the Data Display ............................................................................................. 68 
13.2.6. 
Footnotes .................................................................................................................... 70 
14. QUALITY CONTROL ..................................................................................... 72 
15. MOCK SHELLS OF TABLES, FIGURES, AND LISTINGS ........................... 73 
 
 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AC 
absolute counts 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase 
ATC 
anatomical therapeutic chemical 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BUN 
blood urea nitrogen 
C1D1 
cycle 1, day 1 
C#D# 
cycle #, day # 
CBC 
complete blood count 
CD 
cluster of differentiation 
CI 
confidence interval 
CL 
serum drug clearance 
Clast 
the last observed quantifiable concentration 
CM 
concomitant medication 
Cmax 
maximum observed concentration 
CR 
complete response 
CSR 
Clinical study report 
CTCAE 
common terminology criteria for adverse events 
Ctrough 
trough concentrations 
DLT 
dose-limiting toxicity 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
standard 12-lead electrocardiogram 


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Abbreviation 
Description 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ET 
early termination 
ECG 
electrocardiogram 
F 
fold expansion of circulating CD8 T cells, Tregs, and NK cells  
(day 1 pre-infusion as baseline levels) 
FCBmax 
maximum observed fold change from baseline in serum 
concentration (Day 1 pre-infusion as baseline levels) 
GCP 
Good Clinical Practice 
iORR 
immune overall response rate 
i- 
immune- 
iAE 
immune adverse event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iCR 
immune complete response 
iDCR 
immune disease control rate 
IDMC 
Independent Data Monitoring Committee 
iDOR 
immune duration of response 
IFN 
interferon 
IL-2 
interleukin-2 
IL-2R 
interleukin-2 receptor 
iORR 
immune overall response rate 
iPD 
immune progressive disease 
iPFS 
immune progression-free survival 


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Abbreviation 
Description 
iPR 
immune partial response 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
iSD 
immune stable disease 
IV 
intravenous or intravenously 
L1 
Ligand-1 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
λz 
terminal elimination rate constant 
Max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
minimum 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer [cells] 
N/A 
not applicable 
NSCLC 
non–small-cell lung cancer 
ORR 
overall response rate 
PCS 
potentially clinically significant 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death ligand-1 
PDNC 
protocol deviation and non-compliance 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 


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Abbreviation 
Description 
PTT 
partial thromboplastin time 
QTcF 
QT interval corrected by the Fridericia Correction Formula 
RCC 
renal cell carcinoma 
RCD8 
ratio of CD8 cells to Tregs (day 1 pre-infusion as baseline levels) 
RCD8, max 
maximum RCD8 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNK 
Ratio of NK cells to Tregs (day 1 pre-infusion as baseline levels) 
RNK, max 
maximum RNK 
RP 
relative percentage 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SE 
standard error 
SI 
standard international system of units 
SOC 
system organ class 
SOP 
standard operating procedure 
SRC 
safety review committee 
t1/2 
terminal elimination half-life 
TBD 
To be determined 
TEAE 
treatment-emergent adverse event 
TIL 
Density of tumor-infiltrating lymphocytes 
TLF 
table, listing and figure 
tmax 
time to Cmax 
TME 
tumor microenvironment 
TNF 
tumor necrosis factor 
tCD8, max 
time to maximum RCD8 
tNK, max 
time to maximum RNK 


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Abbreviation 
Description 
TTR 
time to response 
Tregs 
regulatory T cells 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
vs 
versus 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential  
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the summary tables, 
data listings and figures (TLFs) which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives described in the latest study protocol. 
2.1. 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses and is responsible for the production 
and quality control of tables, figures and listings (TLFs) detailed in this SAP text/Mock 
tables for safety and anti-tumor endpoints.  
Alkermes will be responsible for pharmacokinetic (PK), blood-related pharmacodynamics 
and immunogenicity analyses and reporting. Syneos will be responsible for tumor-related 
pharmacodynamics (PD) listing.  
STDM and ADaM data files for tumor-related PD datasets that contain tissue biomarker 
end points will be produced by Syneos Health.  Only STDM data files for PC, blood-related 
PD, and ADA datasets will be produced by Syneos Health. All the PK, ADA and blood-
related PD analyses will be specified in a separate analysis plan. 
2.2. 
TIMINGS OF ANALYSES 
The study will be conducted in 3 parts: Part A, a dose-escalation monotherapy part; Part 
B, a dose-expansion monotherapy part; and Part C, a combination therapy part with 
pembrolizumab. An Extension Phase is planned for subjects completing or who have 
completed 1 year of treatment in Part B or in Part C. There is one electronic data capture 
(EDC) database for Part A, Part B, and Part C together. All analysis specified in this SAP, 
including antitumor activity and safety, will be conducted.  
No formal interim analysis is planned with respect to stopping the study early or for lack 
of antitumor activity purposes. Interim data cuts and analysis will be conducted to support 
abstract submissions, conference presentations, and/or manuscript(s). 
The cut-off date of final analysis will be determined by the sponsor when more than 90% 
enrolled patients discontinued the treatment and all responders have been followed at 
least 6 months. A full set of SAP defined TLFs will be produced and used for preparing the 
clinical study report (CSR).   
Responses in each N1 stage will be assessed to determine whether progression to the N2 
stage is warranted. 


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3. 
STUDY DESIGN 
3.1. 
PRIMARY OBJECTIVE 
• 
To investigate the safety and tolerability of ALKS 4230 and to determine the 
MTD and the RP2D of ALKS 4230 in subjects with advanced solid tumors who 
are refractory or intolerant to therapies known to provide clinical benefit (Part 
A) 
• 
To assess the safety profile and characterize antitumor activity by overall 
response rate (ORR) of ALKS 4230 at the RP2D in subjects with melanoma or 
renal cell carcinoma (RCC) (Part B) 
• 
To characterize the safety profile and antitumor activity by ORR of ALKS 4230 
administered IV in combination with pembrolizumab in subjects with advanced 
solid tumors (Part C) 
• 
To describe the dose-limiting toxicity (DLT) of ALKS 4230 (Part A) 
 
3.2. 
SECONDARY OBJECTIVES 
• 
To characterize the clinical PK profile and immunogenicity of ALKS 4230 alone 
(Part A and Part B) and in combination with pembrolizumab (Part C) 
• 
To investigate the clinical pharmacodynamic effects of ALKS 4230 alone (Part 
A and Part B) and in combination with pembrolizumab (Part C) 
• 
To describe any antitumor activity and responses observed with ALKS 4230 
(Part A) 
• 
To evaluate duration of response (DOR), durable response rate (DRR), and time 
to response for subjects treated with ALKS 4230 in each of the expansion 
cohorts (Part B) and in combination with pembrolizumab (Part C) 
 
3.3. 
EXPLORATORY OBJECTIVES 
• 
To describe changes in post-treatment subject blood and/or tumor tissue 
samples as compared to baseline/pre-treatment samples (Part B) 
• 
 
 
 
 
 
 
 


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3.4.
BRIEF DESCRIPTION
This is a global, multicenter, open-label, Phase 1/2 study. The study will be conducted in 
3 parts: Part A, a dose-escalation monotherapy part; Part B, a dose-expansion 
monotherapy part; and Part C, a combination therapy part with pembrolizumab, as seen 
in the figure and table below. An Extension Phase is planned for subjects completing or 
who have completed 1 year of treatment in Part B or in Part C.
Figure 1: Overall Study Design Schematic
A)


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B)
Abbreviations: L1=ligand-1;, EOT=End of Treatment;, NSCLC=non–small-cell lung cancer;, PD 1=programmed death 
receptor-1;, RCC=renal cell carcinoma;, SCCHN=squamous cell carcinoma of the head and neck;, TBD=to be determined.
a Rollover subjects from Part A or Part B to Part C need to complete 1 year of treatment in Part C before entering the 
Extension Phase. 
b Subjects in Part C are eligible to receive combination treatment for a maximum of 2 years of treatment in total (the 
initial phase plus the Extension Phase of Part C). Subjects may continue ALKS 4230 as a monotherapy beyond the maximum 
of 2 years of treatment — both in Part B by continuing treatment or in Part C by switching to monotherapy.
Note: (Figure 1A): If a dose higher than 6 μg/kg of ALKS 4230 is found to be tolerable for Part A, that dose may be used in 
Part B or Part C.


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Study Design Overview 
Portion of the Study 
Cohort 
ALKS 4230 
Dose 
(µg/kg/day) 
Dose Escalation (Part A)a 
1 
0.1 
2 
0.3 
3 
1 
4 
3 
5 
6 
6 
8 
7 
10 
8 
12 
9 
14 
Dose Expansion (Part B) 
(+ Extension Phaseb) 
Melanomaa 
RP2D 
RCC 
RP2D 
Combination Therapy 
(Part C) 
(+ Extension Phaseb) 
ALKS 4230 1 μg/kg/day safety run-in 
1 
ALKS 4230 3 μg/kg/day safety run-in 
3 
C1: PD-1/L1 unapproved tumor types 
3c 
C2: PD-1/L1 approved tumor types (PD-1/L1 
pretreated) 
3c 
C3: PD-1/L1 approved tumor types (PD-1/L1 
treatment naive) 
3c 
C4: Rollover 
3c 
C5: Melanoma 
6c 
C6: NSCLC 
6c 
C7: SCCHN 
6c 
Abbreviations: DLT=dose-limiting toxicity, NSCLC=non–small-cell lung cancer, PD-1=programmed death receptor-1, PD-
L1=programmed death ligand-1, RCC=renal cell carcinoma, RP2D=recommended Phase 2 dose, SCCHN=squamous cell 
carcinoma of the head and neck, TBD=to be determined. 
a No more than 5 ocular melanoma subjects may be enrolled into this cohort. 
b For subjects receiving clinical benefit from the treatment who are completing or have completed 1 year of treatment 
in Part B or Part C. Rollover subjects from Part A or Part B to Part C need to complete 1 year of treatment in Part C 
before entering the Extension Phase. 
c A subject’s ALKS 4230 doses may be reduced by one dose level as needed at the discretion of the Investigator. 


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Dose Escalation – Part A 
In the dose-escalation part of the study, subjects with advanced solid tumors will receive 
ALKS 4230 by IV administration daily for 5 days, followed by a period off treatment in 
repeating cycles. During Cycle 1, the period off treatment will be 9 days, resulting in a 
cycle length of 14 days (2 weeks). Cycle 2 and subsequent cycles will have a period off 
treatment of 16 days, resulting in a cycle length of 21 days (3 weeks) for each cycle. For 
the first 2 treatment cycles, subjects will receive ALKS 4230 as inpatients at a medical 
facility with access to medical support measures and to the intensive care unit, if needed. 
In the absence of DLTs, subjects who remain in the study may receive subsequent doses 
of ALKS 4230 on an outpatient basis. 
In dose escalation, cohorts in the study will use a standard 3+3 study design with 3 to 6 
subjects per cohort to receive ALKS 4230 at specific dose levels described in Figure 1. The 
starting dose of 0.1 µg/kg/day was selected based on the minimal anticipated biologic 
effect level. Doses in subsequent cohorts will be increased until the optimal biologic dose 
is identified, or the maximum tolerated dose is reached. Additional dose levels will be 
considered if the RP2D or maximum tolerated dose (MTD) has not been reached within 
the proposed dose range. 
During dose escalation, each cohort will be evaluated for safety and tolerability using a 
3+3 study design with allowance for over-enrollment with 4 to 7 subjects and a minimum 
of 3 evaluable subjects per cohort to receive IV ALKS 4230 at the specified dose and 
schedule. If none of the 3 subjects experiences a DLT, then the next dose level will open 
for enrollment. If 1 of the 3 subjects experiences a DLT, then 3 additional subjects will 
be enrolled at the same dose level. If no additional DLTs are observed, then the next dose 
level will open for enrollment. 
If 2 or more subjects experience DLTs at a dose level, no further dose escalations will 
occur. One or more lower dose level(s) may be tested in search of the maximum tolerated 
dose, defined as the dose level immediately below that in which ≥2 of 6 subjects 
experience DLTs. Prior to any dose escalation, a teleconference of the Safety Review 
Committee (SRC), to include at a minimum the study investigators who have enrolled 
subjects and the Sponsor’s Medical Monitor, will be convened to review the safety data 
from the current cohort and to decide if dose escalation is warranted. An interim review 
of the safety data to guide the selection of the RP2D is planned prior to the start of Part B 
of the study using data from subjects enrolled in Part A. RP2D was determined to be 6 
ug/kg. 
 
Dose Expansion – Part B 
After the RP2D is determined, the second part of the study (i.e., Part B) will begin. In 
this part of the study, up to 41 subjects with melanoma (including no more than 5 ocular 
melanoma subjects) and up to 41 subjects with RCC may be enrolled to receive ALKS 4230 
at the RP2D. Enrollment to these cohorts will follow a PR (unconfirmed) Simon’s two-
stage design enrollment as outlined below. Response assessments will be based on the 
RECIST guidelines. 
 


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Simon’s Two-stage Design Enrollment for Subjects in Part B 
  
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if 
N2 
Total 
Expansion Cohort B1: 
Refractory RCC 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Expansion Cohort B2: 
Refractory Melanomaa 
5% 
20% 
21 
≥2 PR/CR 
20 
41 
Abbreviations: CR=complete response; PR=partial response; RCC=renal cell carcinoma 
a No more than 5 ocular melanoma subjects may be enrolled into this cohort. 
 
Combination Therapy - Part C 
In the third part of the study (Part C), subjects will receive ALKS 4230 in combination 
with pembrolizumab. Part C will run independently of and concurrently with monotherapy 
Part A and Part B.  
A 3- to 6-subject run-in phase will be utilized to assess the safety of ALKS 4230 in 
combination with pembrolizumab. During the safety run-in phase, subjects may be 
enrolled with any tumor type as described in the nonrollover cohorts. Rollover subjects 
(Cohort 4) are not eligible to participate in the safety run-in phase of Part C.  
During the safety run-in phase, the first 3 subjects will receive ALKS 4230 at the dose 
level of 1 µg/kg/day. The first subject enrolled at the 1 µg/kg/day dose level will be 
monitored as a sentinel subject. This sentinel subject will be observed for safety for a 
period of 7 days (the sentinel period) from first dose of ALKS 4230. If the sentinel subject 
tolerates treatment adequately during this period, then up to 2 additional subjects may 
be enrolled into the 1 µg/kg/day dose level. If all 3 subjects tolerate therapy adequately 
through their first 21-day cycle as assessed by the Safety Review Committee, then the 
study will progress to the 3 µg/kg/day dose level. At the discretion of the Safety Review 
Committee, an additional 3 subjects may be enrolled at the 1 μg/kg/day dose level to 
further assess safety prior to opening enrollment at the 3 μg/kg/day dose level.  
Once the safety run-in phase at the 1 µg/kg/day dose level is complete and the Safety 
Review Committee has agreed to proceed to the 3 µg/kg/day dose level, the first subject 
will be enrolled at the 3 µg/kg/day dose level and will be observed for 7 days as a sentinel 
subject. If this subject tolerates treatment adequately for 7 days, then up to 2 additional 
subjects may be enrolled in the following week. If the second and third subjects tolerate 
the 3 µg/kg/day dose level adequately for 7 days, then 3 additional subjects can be 
enrolled beginning the following week.  
If the first 6 subjects tolerate therapy adequately for their first 21-day cycle as assessed 
by the Safety Review Committee, then enrollment into expansion Cohorts C1, C2, C3, and 
C4 will be open without restriction in the rate of enrollment at the dose determined by 
the Safety Review Committee. 
Up to 20 subjects will be enrolled into each of Cohorts C1, C2, and C3 based on their 
tumor type and prior treatment with programmed death receptor-1/programmed death 
ligand-1 (PD-L1) pathway inhibitors as described in the inclusion criteria. Subjects with 
RCC or melanoma will not be eligible for enrollment in Cohorts C1, C2, or C3. Subjects on 


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ALKS 4230 monotherapy in Part A or Part B who have experienced disease progression 
after a minimum of 2 cycles or SD after a minimum of 4 cycles and who are able to tolerate 
treatment with combination therapy are eligible for treatment in Part C, Cohort C4. 
Patients who have PR or CR on monotherapy are ineligible to rollover unless 
demonstrating progressive disease. 
Subjects will receive 200 mg of pembrolizumab every 3 weeks in combination with 
ALKS 4230 by IV administration daily for 5 days, followed by a period off treatment of 
16 days, resulting in a cycle length of 21 days (3 weeks) for each cycle.  
Once a RP2D is determined for monotherapy, enrollment into Cohorts C5, C6, and C7 will 
open. Should monotherapy doses above 6 µg/kg/day ALKS 4230 be shown to be tolerated, 
then combination dose escalation may continue for all subjects. In Cohorts C5, C6, and 
C7, up to 31 subjects with melanoma, up to 50 subjects with non–small-cell lung cancer 
(NSCLC), and up to 47 subjects with squamous cell carcinoma of the head and neck may 
be enrolled to receive ALKS 4230 in combination with pembrolizumab at the ALKS 4230 
RP2D. Enrollment to these cohorts will follow a partial response (unconfirmed) Simon’s 
two-stage enrollment as outlined below. Response assessments will be based on the 
RECIST and iRECIST guidelines. 
 
Simon’s Two-stage Design Enrollment for Subjects in Part C 
  
Undesirable 
Rate 
Desirable 
Rate 
N1 
Enroll More if N2 
Total 
C5: Melanoma 
40% 
55% 
27 
≥12 PR/CR 
26 
53 
C6: NSCLC 
13% 
27% 
18 
≥3 PR/CR 
24 
42 
C7: SCCHN 
15% 
30% 
17 
≥3 PR/CR 
19 
36 
Abbreviations: CR=complete response; NSCLC=non–small-cell lung cancer; PR=partial response; SCCHN=squamous cell 
carcinoma of the head and neck 
 
If the RP2D for the combination subjects in Cohorts C5, C6, and C7 is determined by the 
Safety Review Committee to be 6 μg/kg/day or above, intrapatient dose escalation may 
be considered for subjects in Cohorts C1, C2, C3, and C4 who had been assigned to the 
1 μg/kg/day or 3 μg/kg/day dose levels and had adequately tolerated the combination 
therapy. 
 
Planned Number of Subjects for Part C 
Expansion Cohort: Tumor (Setting) 
Number of Subjects 
C1: PD-1/L1 unapproved tumor typesa 
Up to 20 
C2: PD-1/L1 approved tumor types (PD-1/L1 treatment 
pretreated)a 
Up to 20 
C3: PD-1/L1 approved tumor types (PD-1/L1 treatment naive)a Up to 20 
C4: Monotherapy Rollover 
Not applicable 


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Expansion Cohort: Tumor (Setting) 
Number of Subjects 
C5: Melanoma 
Up to 53 
C6: NSCLC 
Up to 42 
C7: SCCHN 
Up to 36 
Abbreviations: C=Cohort; NSCLC=non–small-cell lung cancer; PD-1/L1=programmed death receptor-1/programmed death 
ligand-1; RCC=renal cell carcinoma; SCCHN=squamous cell carcinoma of the head and neck 
a Subjects with RCC or melanoma are not eligible for enrollment in Cohorts C1, C2, and C3. 
 
Extension Phase (Part B and Part C only) 
An Extension Phase is planned for subjects receiving clinical benefit from the treatment 
who are completing or have completed 1 year of treatment in Part B or in Part C. The 
Extension Phase will allow for assessment of long-term effectiveness, immunogenicity, 
and safety information in subjects receiving ALKS 4230 monotherapy or ALKS 4230 in 
combination with pembrolizumab, while minimizing the burden of repeated assessments 
for subjects and investigators. 
Subjects completing 1 year of treatment will enter the Extension Phase after Cycle 18. 
The subjects who are already beyond 1 year of treatment will enter the Extension Phase 
immediately and will start following the Schedule of Assessments of the Extension Phase. 
The 1-year treatment period before the Extension Phase is non-cumulative, ie, in case of 
rollover from Part A or Part B to Part C, subjects need to complete 1 year of treatment 
in Part C before entering the Extension Phase. 
Subjects in Part C are eligible to receive combination treatment for a maximum of 2 years 
of treatment in total (the initial phase plus the Extension Phase of Part C). Subjects may 
continue ALKS 4230 as a monotherapy beyond the maximum of 2 years of treatment — 
both in Part B by continuing treatment or in Part C by switching to monotherapy. Subjects 
will remain on the same dose and schedule when entering the Extension Phase. 
 
3.5. 
SUBJECT SELECTION 
The dose-escalation portion of the study (Part A) will enroll subjects with advanced solid 
tumors. In the monotherapy dose-expansion portion of the study (Part B), subjects with 
melanoma or RCC will be enrolled. In the combination therapy part of the study (Part C), 
subjects will be enrolled into 1 of the 7 predefined cohorts, and some subjects may be 
enrolled in the rollover cohort from Part A or Part B. Each subject must meet all of the 
inclusion and none of the exclusion criteria to participate in this study. 
 
3.5.1. 
Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to participate in this study. 


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1. The subject or the subject’s legal representative is willing and able to provide 
written informed consent. 
2. The subject is aged ≥18 years. 
3. For the dose-escalation portion of the study, the subject has a diagnosis of an 
advanced solid tumor; for the dose-expansion portion of the study (Part B), the 
subject has a diagnosis of melanoma or RCC. 
4. In Part A, all subjects must have an advanced solid tumor (including lymphomas) 
that is refractory or, in the judgment of their physician, intolerant to established 
therapies known to provide clinical benefit for the malignancy in question. In Parts 
B and C, all subjects must have an advanced solid tumor and have had the 
minimum prior lines of therapy as defined by the specific cohort into which the 
subject will enroll.  Treatment with prior immunotherapy is permitted, with the 
exception of subjects enrolling into C3, the PD-1/L1 approved tumor types (PD-
1/L1 treatment naive) cohort; C5, the Melanoma cohort; and C7, the Squamous 
Cell Carcinoma of the Head and Neck cohort who are not permitted to have 
received prior treatment with an anti-PD-1/L1 therapy.  
5. Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination 
therapy part (Part C) of the study must have at least 1 lesion that qualifies as a 
target lesion based on RECIST. 
6. Subjects enrolled in the dose-expansion monotherapy part (Part B) or combination 
therapy part (Part C) of the study must agree to provide archival tumor tissue 
biopsy sample(s). The archival tumor tissue sample does not have to be obtained 
prior to enrollment into the study, however every effort should be made to submit 
the archived tissue within 30 days of study enrollment.  
7. Subjects enrolled in the combination therapy part (Part C) of the study must have 
completed the last dose of any broad-spectrum antibiotic at least 30 days prior to 
first dose (Cycle 1, Day 1). 
8. Subject is ambulatory with an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 and an estimated life expectancy of at least 3 months. 
9. Subjects must have adequate hematologic reserve as evidenced by: 
• 
Absolute neutrophil count (ANC) of ≥1000/µL,  
• 
Absolute lymphocyte count of ≥500/µL, 
• 
Platelet count of ≥75,000/µL, and 
• 
Hemoglobin of ≥9 g/dL (subjects may be transfused to this level if necessary). 
10. Subjects must have adequate hepatic function as evidenced by aspartate 
transaminase and alanine transaminase values ≤3 × the upper limit of normal (ULN) 


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(≤5 × the ULN if the liver is known to be involved by metastatic disease) and serum 
total bilirubin values of ≤1.5 × ULN (≤2 × ULN for subjects with known Gilbert’s 
syndrome) for the reference laboratory. 
11. Subjects must have adequate renal function as evidenced by a serum creatinine 
≤1.5 × the ULN for the reference laboratory or a calculated creatinine clearance 
of ≥60 mL/min by the Cockroft-Gault equation. 
12. For patients with underlying chronic lung disease, and/or lung primary or 
metastatic disease, and/or pleural effusions, room air oxygen saturation must be 
≥92%. 
13. Subjects must be recovered from the effects of any previous chemotherapy, 
immunotherapy, other prior systemic anticancer therapy, radiotherapy, or surgery 
(i.e., toxicity no worse than Grade 1 [Grade 2 alopecia and treatment-associated 
peripheral neuropathy are acceptable]). 
14. Subjects who have received standard or investigational agents 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 the investigational agent 
is not known. Shorter wait periods may be permitted after discussion with the 
Medical Monitor. 
15. Women of childbearing potential (WOCBP) must have a negative pregnancy test 
(serum or urine) within 7 days of the start of treatment, and on Day 1 before the 
first dose is administered. A woman is considered as a WOCBP (fertile) following 
menarche and until becoming postmenopausal unless permanently sterile. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
16. Meets contraceptive requirements defined in the protocol. Women of childbearing 
potential and men (if their sexual partners are WOCBP) must use at least 2 highly 
effective forms of birth control, at least 1 of which is considered highly effective, 
throughout the study if they are heterosexually active.  
In addition to the criteria listed above, to participate in Part B or Part C of the study, 
subjects must meet the following Part B or Part C tumor types of inclusion criteria to 
enroll into the cohorts identified below. 
Additional Inclusion Criteria for Part B Melanoma Expansion Cohort 
Subjects must have advanced melanoma. Subjects must have received an immune 
checkpoint inhibitor (e.g., anti-PD-(L)1 with or without anti-CTLA-4) and, if appropriate, 
a molecularly targeted agent (e.g., BRAF inhibitor if BRAF-mut), and no more than one 
prior cytotoxic chemotherapy. Patients previously treated with checkpoint inhibitor 
either as single-agent or in a combination regimen must have experienced objective 


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response or stable disease (by RECIST or iRECIST as best overall response); patients with 
progressive disease as best response are excluded. 
Additional Inclusion Criteria for Part B Renal Cell Carcinoma Expansion Cohort 
Subjects must have advanced RCC. Subjects may have received an PD-1 or PD-L1-immune 
checkpoint inhibitor, either given as a monotherapy or in combination with a CTLA-4 
inhibitor or in combination with a VEGFR-TKI and no more than two prior systemic 
therapies, including the checkpoint inhibitor-based regimen. Patients previously treated 
with checkpoint inhibitor either as single-agent or in a combination regimen must have 
experienced objective response or stable disease (by RECIST or iRECIST as best overall 
response); patients with progressive disease as best response are excluded. 
Additional Inclusion Criteria for Expansion Cohort C1: PD-1/L1 Unapproved Tumor 
Types 
Subjects who have tumors (excluding RCC and melanoma) that have progressed following 
chemotherapy, and whose tumor types are not approved for treatment with 
pembrolizumab, may be entered in Part C, Cohort C1, if they meet the 
inclusion/exclusion criteria specified. 
Additional Inclusion Criteria for Expansion Cohort C2: PD-1/L1 Approved Tumor Types 
(PD-1/L1 Pretreated): Approved Tumor Types are Based on US FDA Label 
Subjects who have tumor types (other than melanoma and NSCLC, see Cohorts C5 and C6; 
subjects with RCC are not eligible) that are approved for treatment with pembrolizumab 
and have progressed on anti-PD-1/PD-L1 treatment may be entered in Part C, Cohort C2, 
if they meet the other inclusion/exclusion criteria specified.  
Additional Inclusion Criteria for Expansion Cohort C3: PD-1/L1 Approved Tumor Types 
Cohort (PD-1/L1 Treatment Naive): Approved Tumor Types are Based on US FDA Label 
Subjects who have tumors (excluding RCC and melanoma) that have progressed following 
chemotherapy and whose tumor types are approved for treatment with pembrolizumab 
may be entered in Part C, Cohort C3, if they have not received treatment with an anti-
PD-1/PD-L1 antibody and if they meet the other inclusion/exclusion criteria specified.  
Additional Inclusion Criteria for Expansion Cohort C4: Monotherapy Rollover (Rollover 
Subjects from Part A or Part B) 
Subjects on ALKS 4230 monotherapy in Part A or Part B who have experienced disease 
progression after a minimum of 2 cycles or SD after a minimum of 4 cycles and who are 
able to tolerate treatment with combination therapy are eligible for treatment in Part C, 
Cohort C4. Patients who have PR or CR on monotherapy are ineligible to rollover unless 
demonstrating progressive disease. 


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Additional Inclusion Criteria for Expansion Cohort C5: Melanoma 
Subjects with unresectable locally advanced (Stages IIIB, IIIC, and IIID) or distantly 
metastatic (recurrent or de novo Stage IV) invasive cutaneous or mucosal melanoma that 
is measurable and who have not received prior treatment for advanced disease and who 
meet the other inclusion/exclusion criteria may be considered for Part C, Cohort C5. BRAF 
mutation-positive patients are eligible without prior treatment or after failure of BRAF-
directed inhibitor therapy. Patients treated with prior adjuvant therapy with approved 
agents are also eligible, provided they did not have a recurrence within the 6 months of 
completing adjuvant treatment. 
Additional Inclusion Criteria for Expansion Cohort C6: Non–Small-Cell Lung Cancer 
Subjects with Stage IIIB or IV NSCLC who have been treated with anti-PD-1/PD-L1 therapy 
either as single-agent or in combination with a chemotherapy regimen who responded to 
therapy or who had stable disease (SD) before progression after a minimum of 120 days 
of treatment and who meet the other inclusion/exclusion criteria may be considered for 
Part C, Cohort C6. 
Additional Inclusion Criteria for Expansion Cohort C7: Squamous Cell Carcinoma of the 
Head and Neck 
Subjects with recurrent and/or distantly metastatic squamous cell carcinoma of the head 
and neck who have not received anti-PD-1/PD-L1 therapy and who meet the other 
inclusion/exclusion criteria specified may be considered for Part C, Cohort C7. 
 
3.5.2. Exclusion Criteria 
Each subject must not have any of the following conditions to be qualified to participate 
in this study. 
1. Subject is currently pregnant or breastfeeding or is planning to become pregnant 
during the study period. 
2. Subjects with an active infection or with a fever ≥38.5°C (≥101.3°F) within 3 days 
of the first scheduled day of dosing  
3. Subjects with active or symptomatic central nervous system metastases unless the 
metastases have been treated by surgery and/or radiation therapy and/or gamma 
knife, the subject has been tapered to a dose of 10 mg of prednisone (or 
equivalent) or less of corticosteroids for at least 2 weeks before the first dose, 
and the subject is neurologically stable. 
4. Subjects with known hypersensitivity to any components of ALKS 4230 


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5. Subjects who require pharmacologic doses of corticosteroids (greater than 10 mg 
of prednisone daily, or equivalent); however, topical, ophthalmologic, and 
inhalational steroids are permitted.  
6. Subjects with mean QT interval corrected by the Fridericia Correction Formula 
values of >470 msec (in females) or >450 msec (in males) at screening; subjects 
who are known to have congenital prolonged QT syndromes; or subjects who are 
on medications known to cause prolonged QT interval on ECG. 
7. Subjects who developed Grade ≥3 autoimmune disorders while on prior 
immunotherapy (e.g., pneumonitis, nephritis, neuropathy). Subjects who have 
immune-mediated endocrinopathies and are stable on hormone replacement 
therapy are not excluded. Subjects who developed autoimmune disorders of Grade 
≤2 may enroll if the disorder has resolved and the subject is off systemic steroids 
for ≥28 days. Subjects who experienced autoimmune colitis as a toxicity of prior 
immunotherapy must undergo screening colonoscopy to rule out ongoing 
inflammation. Vitiligo is not exclusionary.  
8. Subjects with any other concurrent uncontrolled illness, including mental illness 
or substance abuse, which may interfere with the ability of the subject to 
cooperate and participate in the study; other examples of such conditions would 
include unstable or poorly controlled hypertension; unstable angina; myocardial 
infarction, or cerebrovascular accident within 6 months of study entry; New York 
Heart Association Grade 3 or 4 congestive heart failure; chronic obstructive 
pulmonary disease or diabetes mellitus that has required 2 or more 
hospitalizations in the last year; severe peripheral vascular disease; or recent 
serious trauma. 
9. Subjects known to be positive for human immunodeficiency virus, hepatitis B or 
hepatitis C, or active tuberculosis or has a known history of tuberculosis. 
10. Subjects who are employed by Alkermes, Syneos Health, the Investigator, the 
study center (included permanent or temporary contract workers and designees 
responsible for the conduct of the study), or other affiliate of this study or is 
immediate family of an employee of Alkermes, Syneos Health, the Investigator, 
the study center, or other affiliate. Immediate family is defined as a spouse, 
parent, child, or sibling, whether biological or legally adopted. 
11. Subjects with known hypersensitivity to any components of pembrolizumab (Part 
C subjects only) 
12. Subjects who have had a second malignancy within the previous 3 years. This 
criterion does not apply to subjects with an adequately treated basal cell or 
squamous cell skin cancer, carcinoma in situ of the cervix, prostate cancer Gleason 
score <6 with undetectable prostate-specific antigen over the previous 12 months, 
or ductal breast carcinoma in situ with full surgical resection. 


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13. Subjects with dyspnea at rest or requiring oxygen therapy. 
14. Subjects with active autoimmune disease requiring systemic treatment within the 
past 3 months or documented history of clinically severe autoimmune disease that 
requires systemic steroids or immunosuppressive agents. 
15. Subjects who have received systemic immunomodulatory agents within 28 days 
prior to C1D1. Exceptions may be granted on a case-by-case basis by the Medical 
Monitor 
16. Subjects who have received radiotherapy within the last 4 weeks before start of 
study treatment administration, with the exception of limited field palliative 
radiotherapy.  
17. Subjects who have received administration of a live, attenuated vaccine within 
4 weeks before Cycle 1 Day 1.  
18. Prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow 
transplant recipients. 
19. Subjects who have received prior IL-2-based or IL-15-based cytokine therapy. 
 
3.6. 
DETERMINATION OF SAMPLE SIZE 
The number of subjects planned to be enrolled in this study is expected to be 
approximately 140 to 327. This is based on an assumption of approximately 36 to 54 
subjects to be enrolled in Part A, 42 to 82 subjects to be enrolled in Part B, and up to 191 
subjects to be enrolled in Part C. 
Number of Subjects Expected in Each Study Period 
 
Note: Part C rollover subjects do not contribute the total number of subjects exposed to ALKS 4230.  
 
In Part A of the study, the number of subjects per dose level is illustrated in Overall Study 
Design Schematic. The number of subjects to be enrolled in Part A will depend upon the 


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number of dose escalations, which in turn will depend upon the safety profile of ALKS 
4230. If 6 or 7 dose levels are enrolled, then the number of subjects participating in Part 
A is expected to be approximately 36 to 54. 
Part B is designed to enroll subjects in each of 2 cohorts based on tumor type and prior 
therapy. The sample size of each cohort was chosen based on methodology described by 
Simon regarding optimal 2-stage designs for Phase 2 studies (Simon 1989). The intention 
in this study is to enroll cohorts that correspond to the first stage of such a design. The 
assumed alpha is 0.05 and power is 90%. Enrollment to these cohorts will follow a PR 
(unconfirmed) Simon’s two-stage design enrollment as outlined in section 3.4 for Part B. 
Response assessments will be based on the RECIST and iRECIST guidelines. 
 
The sample size of each cohort was chosen based on methodology described by Simon 
regarding optimal 2-stage designs for Phase 2 studies (Simon 1989). The intention in 
this study is to enroll cohorts that correspond to the first stage of such a design. The 
assumed alpha is 0.15 and power is 85%. Any of the following Part C cohorts may be 
stopped early if inadequate activity is observed: 
• 
PD-1/L1 unapproved tumor types cohort (zero responses in the first 15 
subjects) 
• 
PD-1/L1 approved tumor types (PD-1/L1 pretreated) cohort (zero responses in 
the first 15 subjects) 
• 
PD-1/L1 approved tumor types (PD-1/L1 treatment naive) cohort (≤3 objective 
responses in the first 20 subjects) 
The Part C rollover cohort (Cohort 4) is designed to provide access to ALKS 4230 in 
combination with pembrolizumab for subjects initially enrolled into study Part A and Part 
B. It is estimated that between 0 and 54 subjects may potentially enter this cohort. 
Participation in the rollover cohort does not contribute to the overall number of subjects 
exposed to ALKS 4230. The rollover cohort will close to enrollment if the other 3 Part C 
cohorts have closed early due to insufficient antitumor activity. Enrollment to these 
cohorts will follow a partial response (unconfirmed) Simon’s two-stage enrollment as 
outlined in section 3.4 for Part C. 
 
3.7. 
TREATMENT ASSIGNMENT & BLINDING 
Randomization is not planned for this open-label study. 
Blinding is not applicable for this open-label study.  


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3.8. 
ADMINISTRATION OF STUDY DRUG 
3.8.1. ALKS 4230 Dosing and Administration 
ALKS 4230 will be administered IV as a 30-minute infusion 
 
for 5 consecutive days, followed by a period off treatment in repeating cycles. During 
Cycle 1 of Parts A and B, the period off treatment will be 9 days, resulting in a cycle 
length of 14 days (2 weeks). Cycle 2 and subsequent cycles will have a period off 
treatment of 16 days, resulting in a cycle length of 21 days (3 weeks) for each cycle. 
Infusion for each dosing day of each cycle should begin within 2 hours (plus or minus) of 
the infusion start time for Day 1 of that cycle. Emergency resuscitation equipment should 
be available. For the first 2 treatment cycles of Part A, ALKS 4230 will be administered 
inpatient in a medical facility with access to medical support measures and to the 
intensive care unit, if needed. Subjects may be discharged on Day 6 of each of the first 
2 treatment cycles if medically stable. In the absence of DLTs, subsequent treatment 
cycles may be administered on an outpatient basis. For Part B and Part C of the study, 
administration of ALKS 4230 may be done in an outpatient setting. 
In Part C, on days where ALKS 4230 is administered in combination with pembrolizumab, 
ALKS 4230 should be administered as an infusion 60 (±30) minutes after the completion 
of pembrolizumab infusion. For Part C, a subject’s ALKS 4230 doses may be reduced by 1 
dose level as needed at the discretion of the Investigator. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes [-5 
minutes/+10 minutes]). 
ALKS 4230 may be infused using peripheral or central venous access per local standards 
of care and the treating investigator’s judgement. All patients should have adequate 
intravenous access to allow the immediate management of toxicities. Subjects who do 
not have adequate peripheral venous access should have a central venous access device 
placed per local standards of care. 
The amount of drug administered is based on subjects’ body weight as measured at Day 1 
(72 hours) of each cycle. 
Sites must have written procedures in place detailing the healthcare personnel required 
to be on site during subject dosing, the availability of equipment and medications 
necessary to treat an emergency (should it occur) and the process for transferring a 
subject to a medical facility if necessary. 
3.8.2. Pembrolizumab Dosing and Administration 
Pembrolizumab is to be administered as an IV infusion over 30 minutes in a dose of 200 mg 
every 
3 weeks, 
in 
accordance 
with 
the 
prescribing 
information 
(Keytruda 


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[pembrolizumab] USPI). Subjects will be monitored for at least 1 hour for potential acute 
reactions to pembrolizumab prior to administration of ALKS 4230. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible for either drug. However, given the variability of infusion pumps from site to 
site, a window between -5 minutes and +10 minutes is permitted for ALKS 4230 and 
pembrolizumab (i.e., infusion time is 30 minutes [-5 minutes/+10 minutes]). 
Pembrolizumab is to be obtained from the study sites’ pharmacies, from commercial 
supplies, or provided by Sponsor in countries where pembrolizumab is not yet approved. 
 
 
 
 
 


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3.9. 
STUDY PROCEDURES AND FLOWCHART 
The schedules of visits and assessments for Part A, Part B, Part C, and Extension Phase of 
Part B and C can be found in section 8.2 of protocol.  
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY ENDPOINT 
• 
The incidence of DLTs from the first dose through the end of the DLT 
observation period (Part A) 
• 
The incidence and severity of treatment-emergent AEs according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 or higher (Parts A, B, and C) 
• 
ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
version 1.1 (Eisenhauer et al 2009) (Part B and Part C) 
 
4.2. 
SECONDARY ENDPOINTS 
• 
Serum concentrations of ALKS 4230 and descriptive PK parameters  
• 
Presence of anti-ALKS 4230 antibodies in serum 
• 
Immune (i-) ORR (iORR) based on Immune RECIST (iRECIST) guidelines (Seymour 
et al 2017)  
• 
Disease control rate (DCR) based on RECIST guidelines and immune DCR (iDCR) 
based on iRECIST guidelines 
• 
DOR based on RECIST guidelines and immune DOR (iDOR) based on iRECIST 
guidelines 
• 
DRR for Part B and Part C Cohorts C5, C6, C7 only 
• 
Progression-free Survival (PFS) and immune PFS (iPFS) for Part B and Part C 
Cohorts C5, C6, C7 only 
• 
Numbers of circulating CD8 T cells, Tregs, and NK cells in peripheral blood  
• 
Serum concentrations of IL-6 and other cytokines  
 
4.3. 
EXPLORATORY ENDPOINTS 
• 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
4.4. 
ANTITUMOR ACTIVITY ENDPOINTS 
• 
Objective response rate (ORR) based on Response Evaluation Criteria in Solid 
Tumors (RECIST) guidelines version 1.1 and Immune (i-) ORR (iORR) based on 
Immune RECIST (iRECIST) guidelines (Seymour et al 2017) 
• 
Disease control rate (DCR) based on RECIST guidelines and immune DCR (iDCR) 
based on iRECIST guidelines  
• 
Duration of response (DOR) based on RECIST guidelines and immune DOR (iDOR) 
based on iRECIST guidelines 
• 
Progression-free Survival (PFS) based on RECIST and immune PFS (iPFS) based on 
iRECIST for Part B and Part C Cohorts C5, C6, C7 only 
• 
Time to response (TTR) based on RECIST guidelines and immune TTR (iTTR) based 
on iRECIST guidelines 
4.5. 
SAFETY ENDPOINTS  
Safety will be assessed using the following: 
• 
DLTs 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Laboratory Evaluations (hematology, coagulation, chemistry, urinalysis tests) 
• 
Vital Signs (systolic and diastolic blood pressure, pulse, respiratory rate, and oral 
body temperature) 
• 
ECG parameters (overall assessment; heart rate; RR, PR, QRS, and QTc intervals) 
• 
ECOG Performance Status 
4.6. 
TISSUE BIOMARKERS ENDPOINTS  
Collection of fresh tumor samples via biopsy is optional during the study. Subjects with 
accessible tumors who are willing to undergo biopsy should provide samples at baseline 
and while on treatment around C2D8. A punch biopsy is preferred for tissue collection 
from melanoma patients. 


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These samples will be analyzed by immunohistochemistry and/or immunofluorescence for 
markers of immune activation. They can also be used for gene expression analysis using 
method such as NanoString. The tissue biomarker data will be presented in data listings and 
done separately for PART A, B and C respectively.   
 
 


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5. 
ANALYSIS SETS 
5.1. 
SAFETY POPULATION 
In Part A and Part B, the Safety Population will include all subjects who receive at least 
1 dose of ALKS 4230. In Part C, the Safety Population will include all subjects who receive 
at least 1 dose of ALKS 4230 or pembrolizumab. The Safety Population will be used for all 
safety analyses. 
5.2. 
ANTITUMOR EVALUABLE POPULATION 
The Antitumor Evaluable Population consists of all subjects who complete two cycles of 
therapy and have at least one follow-up scan. 
The Antitumor Evaluable Population will be used for the antitumor activity analyses. 
5.3. 
PROTOCOL DEVIATIONS 
All protocol deviations related to study inclusion or exclusion criteria, conduct of the 
trial, subject management, or subject assessment will be listed. The list of protocol 
deviations will be finalized per the protocol deviation and non-compliance (PDNC) 
management plan and will be reviewed by the Sponsor, the principal investigator, the 
study statistician, and the study medical monitor and finalized before database lock. Only 
major protocol deviations will be summarized. 
5.4. 
PHARMACODYNAMIC POPULATION 
The Pharmacodynamic Population consists of all subjects who received at least 1 dose of 
ALKS 4230 and have at least 1 available post-baseline pharmacodynamics measurement. 
Subjects who may have had any AEs or protocol deviations that are deemed to impact the 
pharmacodynamics measurements may be excluded from the pharmacodynamics analysis 
and summary statistics, which will be documented in the clinical study report.  
The Pharmacodynamic Population will be used for the pharmacodynamic parameter 
calculations, graphical displays of individual data, and the listings of cytokine 
concentrations and pharmacodynamic parameters. 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
• 
Data will be summarized for Part A, Part B, and Part C separately when analysis is 
applicable for the part. For Part A, the summary tables will be presented by dose 
cohorts (0.1 µg/kg, 0.3 µg/kg, 1 µg/kg, 3 µg/kg, 6 µg/kg, 8 µg/kg, and 10 µg/kg ALKS 
4230) and overall, and data listings will be ordered by dose cohorts and subject ID. 
For Part B, the summary tables will be presented by expansion cohorts with specified 
tumor types (RCC and Melanoma) and overall, and data listings will be ordered by 
expansion cohorts and subject ID. For Part C, the summary tables will be presented 
by cohorts based on subject’s tumor type and prior treatment with PD-1 or rollover 
from Part A or B (Safety Run-in 1 ug/kg, Cohort 1: PD-1/L1 unapproved tumor types 
plus Safety Run-in 3 ug/kg, Cohort 2: PD-1/L1 approved tumor types (PD-1/L1 
pretreated), Cohort 3: PD-1/L1 approved tumor types (PD-1/L1 treatment naïve), 
Cohort 4: Monotherapy Rollover, Cohort 5: Melanoma, Cohort 6: NSCLC, Cohort 7: 
SCCHN ), and overall, and data listings will be ordered by cohorts and subject ID.  
• 
The continuous variables will be summarized using number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum unless otherwise specified. 
All estimations will include a point estimate and the corresponding 95% confidence 
interval. All mean (arithmetic and geometric) and median values will be formatted to 
1 more decimal place than the measured value. SD values will be formatted to 2 more 
decimal places than the measured value. Minimum and maximum values will be 
presented to the same number of decimal places as the measured value. The 
coefficient of variation (CV) % will be formatted to 1 decimal point.  
• 
The categorical variables will be summarized using frequency counts and percentages 
of subjects. All percentages will be rounded to 1 decimal place. Number and 
percentage values will be presented as xx (xx.x%). 
• 
P-values will be output in the format: “0.xxx”, where xxx is the value rounded to 3 
decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-value 
is returned as >0.999, then it will be presented as >0.999. 
• 
Confidence intervals (CIs) will be presented as 2-sided 95% CIs, unless specified 
differently in specific analyses. 
• 
For concomitant medications and AEs, which are not associated to a visit, the cycles 
are determined based on their start dates. For other collected data, the cycles are 
determined based on their visit dates. When there are multiple laboratory records for 
a scheduled visit, the one closest to the target date (relative to the Day 1 in that 
cycle) will be used for analysis. If there are 2 or more records (for repeated test, for 
example) with the same time period to the target date, the later one will be used for 
analysis unless specified differently in specific analyses.  


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• 
Partial AEs/concomitant medications start/end dates will be imputed on the rules 
specified in Section 6.3.1. 
• 
The cumulative tumor response and AE data will be summarized for subjects who 
enter into the Extension Phase. 
• 
All laboratory data will be reported using international system of units.  
• 
All analyses will be performed using SAS® statistical software package, version 9.4 or 
higher.  
6.2. 
KEY DEFINITIONS 
6.2.1. Cycle 1 Day 1 
Cycle 1 Day 1 (C1D1) is defined as the date of the first dose of ALKS 4230 in the first 
dosing cycle. For rollover patients, C1D1 is the date of first ALKS 4230 dosing for each 
part respectively.    
6.2.2. Enrollment 
A subject is considered enrolled onto the study if a patient signed a consent form. The 
enrollment date is set to consent date. 
Screen failures will not be recorded in the database. 
6.2.3. Treatment Period 
The treatment period starts on C1D1 and lasts until the end of the treatment date 
collected in the database 
6.2.4. Study Day 
The study day is determined relative to C1D1 in the study, while the cycle day is the day 
relative to the first dose date in that cycle. The day of the first dose of study medication 
in Cycle 1 will be defined as Study Day 1. The day prior to the first dose of study 
medication is Study Day -1. There is no Study Day 0. 
6.2.5. Cycle Start/End Day 
The start date of each treatment cycle will be calculated based on study drug exposure 
records for each subject. The start date of the cycle will be the date when the subject 
receives the first study drug of the cycle, noted as S1, S2, S3, etc. For the Lead-In 
Monotherapy cycle, the start date will be the first date when the subject receives ALK 
4230 Monotherapy.  For the combination cycles, the start date will be the first date the 
subject receives the ALK 4230 + Pembrolizumab combination therapy. 


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The end date of each cycle is calculated as the day before the start date of the following 
cycle: ie, Ei = Si+1 - 1. For the last cycle, the end date will be calculated based on the last 
study dose date. The cycle end date is the last dose date + 16 except when cycle 1 is the 
last cycle in Parts A and B, for which the cycle end date is the last dose date + 9. 
6.2.6. Cut-Off Date of Final Analysis 
This study has not specified the treatment duration. For the purpose of final analysis, 
the cut-off date of final analysis will be determined by the sponsor when more than 90% 
enrolled patients discontinued the treatment and all responders have been followed at 
least 6 months.  This will be considered as the main analyses. A full set of SAP defined 
TLFs will be produced and used for preparing the clinical study report (CSR).   
6.2.7. Baseline and Change from Baseline 
Study Baseline 
Baseline value is defined as the last value prior to the first dose of study treatment 
administration. This value could be the pre-infusion assessment on the first dose date or 
the assessment at the screening visit. If multiple values are present for the same date, 
the values from the last assessment will be used as the baseline unless specified. The 
standard 12-lead ECGs will be performed in triplicate 5 minutes apart at all time points 
outlined in the protocol. The median value of the last triplicate ECGs prior to the first 
dose of study treatment will be used for summary purposes. 
Part C Baseline for Rollovers 
Baseline value is defined as the last value prior to the first dose of study treatment 
administration in Part C. This value could be the pre-infusion assessment on the first dose 
date. If multiple values are present for the same date, the values from the last assessment 
will be used as the Part C baseline unless specified. The standard 12-lead ECGs will be 
performed in triplicate 5 minutes apart at all time points outlined in the protocol. The 
median value of the last triplicate ECGs prior to the first dose of study treatment will be 
used for summary purposes. 
The rollover subjects have two baseline values. The study baseline values are used for 
Part A and Part B analysis, and Part C baseline values are used for Part C analysis. 
Absolute change from baseline (CFB) = (post-baseline value – baseline value).  
Fold change from baseline (FCB) = post-baseline value/ baseline value. 
For the purpose of tabulations for lab, ECG and vital sign, the unscheduled post-baseline 
values generally will be excluded from summary tables, but will be included in the listing. 
Unscheduled visits will be considered for analyses of worst CTCAE laboratory grades. 


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6.3. 
MISSING DATA 
All available data of the subjects who withdraw from the study for any reasons will be 
analyzed. There will be no imputation of missing data for the analysis, except for partial 
dates specified below.  
If the date and/or time that an AE started is incomplete, the event will be considered a 
TEAE unless the partial dates/times give sufficient detail in order to prove that the AE 
started prior to the first dose in the study. In such cases the event will not be considered 
a TEAE.  
For rollover subjects, if the date and/or time that an AE started is incomplete, the event 
will not be considered a Part C TEAE unless the partial dates/times give sufficient detail 
to prove that the AE started on or after the first dose of Part C in the study.  
If the date that a medication started is incomplete, the medication will be considered as 
concomitant unless the partial date(s) give sufficient detail in order to prove that the 
medication was started and stopped prior to the day of first dose in the study. In such a 
case, the medication will be considered as prior medication. 
For rollover subjects, if the date that a medication started is incomplete, the medication 
will be considered as Part C concomitant unless the partial date(s) give sufficient detail 
in order to prove that the medication was started and stopped prior to the day of first 
dose of Part C in the study.  
6.3.1. 
Imputation of Missing Adverse Events/Prior or Concomitant 
Medications  
Incomplete Start Date: 
Missing day and month 
• 
If the year is the same as the year of the first dosing date, then the day and month 
of the first dosing date will be assigned to the missing fields. 
• 
If the year is prior to the year of first dosing date, then December 31 will be 
assigned to the missing fields. 
• 
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields. 
Missing day only  
• 
If the month and year are the same as the year and month of first dosing date, 
then the first dosing date will be assigned to the missing day. 


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• 
If either the year of the partial date is before the year of the first dosing date or 
the year of the partial date and the first dosing date are the same but the month 
of partial date is before the month of the first dosing date, then the last day of 
the month will be assigned to the missing day. 
• 
If either the year of the partial date is after the year of the first dosing date or 
the year of the partial date and the first dose date are the same but the month of 
partial date is after the month of the first dosing date, then the first day of the 
month will be assigned to the missing day. 
• 
If the stop date is not missing, and the imputed start date is after the stop date, 
the start date will be imputed by the stop date.  
Missing day, month, and year 
• 
No imputation is needed, and the corresponding AE will be included as a TEAE of 
all study parts to which it is applicable.  
Incomplete Stop Date:  
If the imputed stop date is before the start date, then the imputed stop date will be equal 
to the start date. 
Missing day and month 
• 
If the year of the incomplete stop date is the same as the year of the last dosing 
date, then the day and month of the last dosing date will be assigned to the missing 
fields.  
• 
If the year of the incomplete stop date is prior to the year of the last dosing date 
or prior to the year of the first dosing date, then December 31 will be assigned to 
the missing fields.  
• 
If the year of the incomplete stop date is prior to the year of the last dosing date 
but is the same as the year of the first dosing date, then the first dosing date will 
be assigned to the missing date.  
• 
If the year of the incomplete stop date is after the year of the last dosing date, 
then January 1 will be assigned to the missing fields. 
Missing day only  
• 
If the month and year of the incomplete stop date are the same as the month and 
year of the last dosing date, then the day of the last dosing date will be assigned 
to the missing day.  


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• 
If either the year of the partial date is not equal to the year of the last dosing 
date or the year of the partial date and the last dosing date are the same but the 
month of partial date is not equal to the month of the last dosing date, then the 
last day of the month will be assigned to the missing day.  
6.4. 
VISIT WINDOWS 
Data collected at unscheduled visits that occurred outside the time windows specified in 
the protocol (e.g., postdose laboratory tests done on days not specified in the protocol) 
will be included in the data listings but will not be included in analyses summarized by 
timepoint unless otherwise stated. 
For summaries by time point, if data is collected at multiple time points within a protocol 
specified time window (protocol section 8.2), the result taken at the closest time to the 
planned nominal time point will be used, unless specified otherwise. If this time is equal 
to either side of the nominal time-point for 2 measures, the earlier measure will be taken. 
6.5. 
POOLING OF CENTERS 
Data from all study centers will be combined for analysis. 
6.6. 
SUBGROUPS 
Some analyses by subgroups are planned, for example subgroup analysis based on the 
tumor type. 
6.7. 
HANDLING PHARMACODYNAMICS DATA BELOW THE LOWER LIMIT OF 
QUANTIFICATION OR MISSING 
For pharmacodynamic immunophenotype results, serum cytokine concentration 
summary, individual serum cytokine concentration versus time curves, and mean 
concentration versus time graphs, the following rules will apply: 
• 
Serum cytokine concentration values below the assay’s lower limit of 
quantification (LLOQ) for all time points will be treated as ½ of the LLOQ. 
• 
For baseline with missing values, the fold change from baseline for relevant 
pharmacodynamic parameters will not be calculated. The sampling time of pre-
infusion samples relative to dosing will be treated as zero. 
• 
If the actual time of sampling is missing, the nominal time will be used. 
• 
No further imputation will be applied to any missing values.  


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• 
If one or both AC values are missing at a time point for NK and Treg cells or for CD8 
T and Treg cells, then no ratios (RNK/Treg or RCD8/Treg) will be calculated for the time 
point. 
 
 
 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
The total number of subjects enrolled to each study part will be summarized separately 
for Part A, Part B, and Part C. A summary of subject disposition will be presented for the 
Safety Population, Antitumor Evaluable Population and subjects who discontinued from 
the treatment and discontinued from the study.  
Reasons for treatment discontinuation and study discontinuation will be summarized for 
all subjects with the following categories: 
• 
Adverse event 
• 
Lost to follow-up 
• 
Pregnancy 
• 
Noncompliance resulting in a protocol deviation 
• 
Study terminated by sponsor 
• 
Withdrawal by subject 
• 
Progressive disease 
• 
Clinical progression  
• 
Physician decision  
• 
Rollover from monotherapy to combination therapy (Part C) (this is only applied to 
part A and Part B disposition tables) 
• 
Other 
Subjects’ completion/discontinuation status will be listed, including subject identifier, 
informed consent date, date of completion/early discontinuation and, for those who 
discontinued early, the specific reason(s) for discontinuation. 
Inclusion/exclusion 
criteria 
definitions 
and 
violations 
will 
be 
listed. 
If 
no 
inclusion/exclusion violations are reported, this will be noted in place of the listing. 
Major protocol deviations will be summarized by categories for all subjects. All protocol 
deviations related to study inclusion or exclusion criteria, conduct of the trial, subject 
management, or subject assessment will be listed.  


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7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Age (years), height (cm), weight (kg), and BMI (kg/m2) at baseline will be summarized 
descriptively. Sex, race, ethnicity, BMI category (underweight: < 18.5 kg/m2, normal: 
18.5 - <25 kg/m2, overweight: 25 - <30 kg/m2, and obesity: ≥30 kg/m2), and ECOG 
performance status (0, 1, >1) will be summarized by frequency counts. Body mass index 
is calculated based on weight and height at baseline. 
Demographic data and baseline characteristics (as detailed above) as well as informed 
consent data will be listed. 
Descriptive statistics for prior line of therapy will be summarized.  
7.3. 
CANCER DISEASE HISTORY 
Cancer disease history will be summarized. The number and percentage of subjects in 
each of the following categories will be presented.  
• 
Method of Initial Diagnosis  
• 
Primary Origin of Tumor Type 
The time from initial diagnosis to first dose (years) and time from most recent disease 
progression to first dose (weeks) will be summarized descriptively.  
Cancer disease history will be listed for the Safety Population. 
7.4. 
MEDICAL HISTORY 
Reported medical history terms will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 25.0 or higher. General medical history information will be 
summarized by category of medical history being collected. Medical history will be listed 
for the Safety Population. 
7.5. 
PRIOR SURGERIES AND THERAPIES  
A frequency tabulation of the number of subjects with previous cancer-related surgery, 
radiation therapy, and systemic therapy will be given. In addition, tabulation will be 
provided by location of radiation therapy and type of previous systemic therapy.  
Prior cancer-related surgery, prior radiation therapy, and prior systemic therapy will be 
listed. 


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7.6. 
PRIOR AND CONCOMITANT MEDICATION 
Prior medications will be defined as any medications taken prior to the C1D1. 
Concomitant medications will be defined as medications ongoing or stopped on or after 
the date of the first dose of ALKS 4230. 
Prior and concomitant medications will be coded with World Health Organization (WHO) 
Drug Dictionary version March 2016 or higher. 
The number and percentage of subjects using each concomitant medication will be 
displayed together with the number and percentage of subjects using at least 1 
medication within each medication group and subgroup. Prior medications will be 
presented in a data listing only. 


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8. 
EFFICACY 
Antitumor activity will be determined by the measurement of extent of known disease at 
baseline and approximately every 5 to 6 weeks, following each even-numbered treatment 
cycle. Appropriate radiological procedures (computed tomography (CT) scanning, 
magnetic resonance imaging (MRI), radionuclide imaging) should be conducted to 
evaluate areas of disease. Superficial skin tumors will be measured with calipers and 
photographed for evaluation. It is requested that the initial method of measurement be 
maintained throughout the course of the study. The determination of response will be 
conducted according to the standard RECIST 1.1 criteria as well as the iRECIST for part A, 
B, and C.  
According to the guidelines for RECIST 1.1, tumors are assessed as complete response 
(CR), partial response (PR), stable disease (SD), or progressive disease (PD). 
Responses assigned using iRECIST have a prefix of “i” e.g., “immune” complete response 
(iCR) or partial response (iPR), stable disease (iSD), and unconfirmed progressive disease 
(iUPD) or confirmed progressive disease (iCPD) to differentiate them from responses 
assigned using RECIST 1.1. 
RECIST 1.1 and iRECIST have the same overall response until RECIST 1.1 progressive 
disease (PD) is reached. The iRECIST CRF will be used if patient has a RECIST disease 
progression and clinical stable, and continues on treatment. The principles used to 
establish objective tumour response are largely unchanged from RECIST 1.1, but the 
major change for iRECIST is the concept of resetting the bar if RECIST 1.1 progression is 
followed at the next assessment by tumour shrinkage. iRECIST defines iUPD on the basis 
of RECIST 1.1 principles; however, iUPD requires confirmation.  
As the iRECIST CRF page is only triggered after patients has iUPD and clinical stable. In 
the process to create iRECIST analysis dataset, the tumor response data before iUPD will 
be copied from RECIST 1.1 
To note, determination of response is conducted according to iRECIST beginning with 
Amendment 10. Prior to Amendment 10 it was conducted by IrRC.  
In studies with immunotherapeutic agents, CR, PR, or SD have been shown to occur after 
an increase in tumor burden characterized as PD by RECIST criteria. The conventional 
response criteria such as RECIST may not adequately assess the activity of 
immunotherapeutic agents. PD evaluated radiologically may not mean therapeutic 
failure, as responses to immune therapies may occur after conventional PD. The 
appearance of measureable antitumor activity may take longer for immune therapies than 
for cytotoxic therapies. With immunotherapeutic agents, there should be allowance for 
clinically insignificant PD, defined as small new lesions in the presence of other responsive 
lesions, which may occur even though the subject is responding to the immunotherapy. 
Stable disease may also represent antitumor activity with iRECIST. Therefore, RECIST and 


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iRECIST will be used to ensure a more comprehensive evaluation of tumor response for 
ALKS 4230. 
Efficacy endpoints based on irRC and iRECIST will not be derived and associated analyses 
will not be performed as the iRECIST was implemented during the middle of the study 
conduct to replace irRC. The sites have not consistently record the iRECIST data which 
could provide misleading information.  
8.1. 
OVERALL RESPONSE RATE (ORR)  
ORR is defined as the proportion of subjects with objective evidence of complete response 
(CR) or partial response (PR) among the number of subjects evaluable for antitumor 
activity based on RECIST.  
At the analysis stage, the best overall response (BOR) will be assigned for each subject as 
the best response recorded after initiation of study treatment, where the confirmation 
of CR or PR is required.  The BOR assignment will follow the table below. 
 
If applicable, responses recorded after initiation of new anticancer treatment will be 
excluded.  
The BOR will be calculated separately for those subjects in the dose-escalation portion 
of the study (Part A), in the dose-expansion portion of the study (Part B), and in the 
combination therapy part of the study (Part C). The BOR will be summarized by cohorts 
for Part A, Part B, and Part C. In addition, the subjects who have SD more than 6 months 
will be summarized. 
Summarization of ORR will be presented by frequency counts, percentage, and 95% CI. 
The CI will be obtained using an exact approach given the small sample size.  


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The sum of the diameters of all target lesions reported at each visit will be graphed by 
spider plot (% change in target lesion over time) and waterfall plot (best % change in 
target lesion). A swimmer plot will be used to display the characteristics of the overall 
responses over time.  
In addition, listings of RECIST overall evaluation, target lesions, non-target lesions, and 
new lesion will be provided. 
8.2. 
DISEASE CONTROL RATE (DCR) 
DCR is defined as the proportion of subjects with objective evidence of CR, PR (where CR 
or PR requires confirmation), or SD (where the SD requires to occur at Cycle 4 or later).  
The DCR will be calculated separately for those subjects in the dose-escalation portion of 
the study (Part A), in the dose-expansion portion of the study (Part B), and in the 
combination therapy part of the study (Part C). 
Summarization of DCR will be presented by frequency counts, percentage, and 95% CI. 
The CI will be obtained using an exact approach given the small sample size. 
8.3. 
DURATION OF RESPONSE (DOR) (PART B AND PART C) 
DOR is defined as the time from the first documentation of response (CR or PR) to the 
first documentation of objective tumor progression or death due to any cause based on 
RECIST.  
The DOR will be calculated for RECIST responders.  
Censored subjects: 
• 
Subjects who are alive and progression free as of the analysis cut-off date will be 
censored at their last evaluable tumor response assessment before initiation of 
any new anticancer treatment.  
• 
Subjects with two or more consecutive missing response assessments prior to 
death or a visit with documented progression will be censored at the last date of 
tumor assessment when the subject was documented to be progression free.  
 
Subjects who never achieve CR or PR prior to starting any new anti-cancer treatment at 
a lesion site will be excluded from the analysis. 
 
If no CR/PR prior to starting any new anti-
cancer treatment 
excluded from the analysis 
If responder (CR/PR) and then PD/death 
Without start of new anticancer 
no censor 


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If responder (CR/PR) and then 
start of new anticancer  
(with PD/death or not, after this start of 
new anticancer) 
date of last evaluable tumor response 
assessment before new anticancer is 
censor date 
If responder (CR/PR) and then PD/death 
Without start of new anticancer 
But with two or more consecutive missing 
response assessments prior to PD/death 
date of tumor assessment when the 
subject was documented to be progression 
free is censor date 
 
For Part B, the DOR will be calculated as follows (in weeks): 
(date of PD /death in Part B – date of first response (CR or PR) in Part B + 1)/7 
For Part C, the DOR will be calculated as follows (in weeks): 
(date of PD/death in Part C – date of first response (CR or PR) in Part C + 1)/7 
The distribution of DOR will be estimated for Part B and Part C using Kaplan-Meier 
methodology. The median point estimate DOR will be provided along with the two-sided 
95% CIs for the antitumor evaluable population. Kaplan-Meier curves will be provided. 
Part A DOR information will be listed only. 
To help in interpretation of the response data, a table with change on the frequency of 
scans may be provided. 
8.4. 
DURABLE RESPONSE RATE (PART B AND PART C) 
Durable response rate is defined as the percentage of patients with an objective response 
(complete or partial response per RECIST1.1) lasting continuously for 6 months and 
starting any time within 12 months of initiating the study drug. The DRR will be 
summarized by each tumor type.  
Summarization of DRR will be presented by frequency counts, percentage, and 95% CI. 
The CI will be obtained using an exact approach given the small sample size. 
Analysis of Durable Response Rate will only be conducted as needed as the data allows. 
8.5. 
PROGRESSION-FREE SURVIVAL (PFS) (PART B AND PART C COHORTS C5, 
C6, C7 ONLY) 
PFS is defined as the time from the first dose of ALKS 4230 to the first documentation of 
objective tumor progression based on RECIST or death due to any cause.  
The protocol stated that the PFS analysis will be only performed for Part B and Part C 
(Cohorts 5-7). The additional PFS analysis in ovarian patients from the PD-L1 unapproved 


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cohort will be conducted as ovarian is identified as one of tumor types to advance further 
clinical development in ALKS 4230 in combination with Pembrolizumab. 
Subjects who do not have disease progression or have not died will be censored at the 
last known time that the subject was progression-free.  
Censored subjects: 
• 
If a subject begins a new anticancer treatment (either systemic or local) prior to 
documented progression or death, or a subject is removed from the study due to 
undocumented clinical disease progression, then the subject will be censored at 
the last assessment where the subject was documented as progression-free prior 
to the intervention.   
• 
Subjects with two or more consecutive missing response assessments prior to a 
visit with documented progression (or death) will be censored at the last date of 
tumor assessment when the subject was documented to be progression free. 
 
If no PD/death 
Without start of new anticancer 
the last known time that the subject was 
progression-free is censor date 
If start of new anticancer prior to 
PD/death or a subject is removed from 
the study due to undocumented clinical 
disease progression 
 
date of last assessment where the subject 
was documented as progression-free prior 
to the intervention is censor date 
If two or more consecutive missing 
response assessments prior to PD/death  
 
date of the last date of tumor assessment 
when the subject was documented to be 
progression free is censor date 
 
 
For Part B, the PFS will be calculated as follows (in weeks): 
(date of PD /death in Part B – first dose date in Part B + 1)/7 
For Part C, the PFS will be calculated as follows (in weeks): 
(date of PD /death in Part C– first dose date in Part C + 1)/7 
The survival distribution of PFS will be estimated using Kaplan-Meier methodology. The 
median RECIST PFS will be provided along with the two-sided 95% CIs based on the 
antitumor evaluable population. In addition, Kaplan-Meier curves will be provided. The 
6-month and one-year PFS rate will be estimated using the Kaplan-Meier estimate. 


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8.6. 
TIME TO RESPONSE (TTR) (PART B AND PART C) 
TTR is defined as the time from the date of first dose of study drug to the first 
documentation of response (CR or PR) based on the RECIST. 
The TTR will be calculated for RECIST responders. 
For Part B, the TTR will be calculated as follows (in weeks): 
(date of first response (CR or PR) in Part B – date of first study drug in Part B + 1)/7 
For Part C, the TTR will be calculated as follows (in weeks): 
(date of first response (CR or PR) in Part C – date of first study drug) in Part C + 1)/7 
The TTR will be summarized with descriptive statistics by cohorts for Part B and Part C. 


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9. 
SAFETY ANALYSES 
The population used for safety analyses will be the Safety Population. Safety will be 
assessed on the basis of AEs, clinical laboratory data, ECG parameters, physical 
examinations, and vital signs. 
9.1. 
EXTENT OF EXPOSURE 
The ALKS 4230 administration profile will be summarized by each part and cohort for the 
safety population with respect to duration of exposure, number of doses by cycle, 
cumulative doses received, number of cycles, average number of ALKS 4230 per cycle, 
relative dose intensity, duration of treatment and duration of study follow-up time.  
Number of patients who missed the dose will also be summarized by planned dosing day 
and by cycle. Data will also be summarized for subjects with any infusion interruptions 
and reason for interruption, and subjects with dose adjustments. 
For rollover subjects from Part A or Part B, subjects will start with 3ug/kg as per protocol. 
However, some subjects might start with 6ug/kg as Part C C1D1 dosing. Therefore, the 
6ug/kg should be used in relative dose intensity calculation in the denominator as planned 
dose. 
In addition, the dose might be adjusted (either increase or decrease the dose) due to 
tolerability or other reasons after C1D1. In the relative dose intensity calculation, C1D1 
dose is carried forward to the end of treatment as planned dose regardless dose changes 
during the treatment period.  
Duration of exposure (days) = last dose date – first dose date + 1. 
Treatment duration (days) = end of treatment (EOT) date – first dose date + 1, in which 
the last cycle end date will replace EOT date if the latter is missing.  
In case of missing last cycle end date for rollover subjects in Part A or Part B, treatment 
duration (days) will be calculated as Part C cycle 1 day 1 date – Part B cycle 1 day 1 date 
+ 1. If rollover subjects missing last cycle end date in Part C, take the last dose date in 
Part C + 16 days as the last cycle end date. 
Relative dose intensity (%) = 100 × [total dose received (ug/kg) / total protocol planned 
dose (ug/kg)].  
Duration of study (days) = end of study (EOS) date – first dose date + 1. 
For those subjects with infusion interruptions, the reason for interruption will be 
summarized. If the subject has multiple interruptions caused by the same reason, the 
subject is only counted once per reason category.  


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Dose reductions and treatment discontinuations will be recorded on the eCRF, along with 
the AE/SAE or DLT that was associated with the change in dosing.  
ALKS 4230 and pembrolizumab will be administered at a medical facility or study center 
by study staff; therefore, compliance is ensured. The treatment compliance will not be 
analyzed. 
9.2. 
DOSE-LIMITING TOXICITIES 
A DLT is defined by any of the following events possibly, probably, or definitely related 
to ALKS 4230 that are observed during the interval from C1D1 through C2D15:  
• 
Grade 4 neutrophil count decreased (neutropenia) that has not recovered to Grade 
2 (≥1,000 cells/mm3) within 15 days of the start of the cycle or requires an urgent 
intervention (e.g., use of hematopoietic colony-stimulating factors) or is 
associated with clinically significant infection. Dosing with ALKS 4230 in the 
current cycle will not be stopped due to neutropenia in the absence of urgent 
intervention or clinically significant infection 
• 
Febrile neutropenia (ANC <1,000 cells/mm3 with temperature >38.3°C [101°F]) 
that persists for more than 48 hours or requires an urgent intervention (eg, use of 
hematopoietic colony-stimulating factors) or is associated with clinically 
significant infection 
• 
Grade 4 thrombocytopenia that does not recover to Grade ≤2 within 15 days of 
the start of the treatment cycle 
• 
Thrombocytopenia with a platelet count <30,000 with clinically significant 
bleeding 
• 
Any Grade 3 cardiac or central nervous system toxicity 
• 
Liver transaminase elevation higher than 8 × ULN or total bilirubin higher than 
6 × ULN that does not recover to Grade ≤2 or baseline within 1 week 
• 
Grade 4 hypoalbuminemia 
• 
Fever >40°C sustained for >24 hours 
• 
Hypotension requiring the use of pressors (eg, phenylephrine or dopamine, 
administered for the purpose of increasing blood pressure) or prolonged 
hospitalization (>48 hours) for hypotension requiring medical intervention 
• 
Grade 3 or higher electrolyte abnormalities that do not recover to Grade ≤1 within 
48 hours following medical management 


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• 
Increase in amylase or lipase that meets 1 of the following criteria: 
o Asymptomatic Grade 4 elevation 
o Asymptomatic Grade 3 elevation that does not resolve within 14 days 
o >3 × ULN with acute severe abdominal pain (other mild symptoms at Grade 
3 will not be considered as DLTs) 
• 
Grade 3 or higher nausea, vomiting, or diarrhea lasting longer than 48 hours 
despite maximum supportive care is a DLT. 
• 
Any other Grade 4 non-hematologic toxicity or any other Grade 3 non-hematologic 
toxicity that does not resolve to Grade ≤2 within 96 hours, other than fatigue or 
anorexia. Fatigue and anorexia will not be considered DLTs. 
• 
Any other toxicity or AE not defined above that results in subject removal from 
the study or discontinuation of dosing by the Investigator (dose delays during Cycle 
2 or later are not considered DLTs) 
Any laboratory value that meets the DLT criteria as described above must be confirmed 
with a second laboratory test for DLT criteria to be met. 
Subjects without a DLT who receive fewer than 10 doses through C2D15 will be replaced 
at the same dose level if the minimum number of evaluable subjects has not been reached 
for the cohort. However, the subject may remain in the study if the Investigator feels the 
risk/benefit ratio is acceptable.  
All DLTs will be summarized by system organ class and preferred term, and by cohort for 
Part A, and a corresponding listing of DLTs-like will be provided for Part A. 
9.3. 
ADVERSE EVENTS 
Adverse events will be analyzed in terms of TEAEs, which are defined as AEs that are 
newly occurring or worsening from the time of the first dose of study drug. Reported AE 
terms will be coded using MedDRA version 25.0 or higher. The severity of the toxicities of 
AEs will be graded according to the NCI CTCAE version 4.03 or higher.  
The severity of toxicities of AE is graded as mild (grade 1), moderate (grade 2), severe 
(grade 3), life-threatening (grade 4), or fatal (grade 5).  
The relationship to study treatment is evaluated as definitely related, probably related, 
possibly related, probably not related, and definitely not related. Events will be classified 
as related vs non-related. A related AE is an event with a relationship to treatment as 
definitely related, probably related, or possibly related to study drug; a non-related AE 
is an event with relationship to treatment as probably not related, or definitely not 


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related. If the relationship to the study treatment is missing, the TEAE will be considered 
to be treatment-related for table summary purposes. 
TEAEs will be summarized by SOC and PT and by cohort. Some outputs with TEAEs based 
on tumor type may be produced for submission purpose. TEAEs with onset after the last 
dose of the study treatment period are attributed to the treatment received during the 
treatment period. Both event and subject counts will be summarized. Subject counts will 
be complemented by percentages calculated using the number of subjects exposed to 
study drug as the denominator. 
The following summaries will be provided: 
• 
An overall summary of the number and percentage of subjects reporting TEAEs, 
serious TEAEs, grade 3 or higher AEs, death, treatment-related TEAEs, and TEAEs 
leading to study discontinuation, leading to treatment discontinuation, leading to 
dose reduction, leading to dose interruption 
• 
TEAEs by SOC and PT (including all severity grades) 
• 
Most common (>= 10%) TEAEs by SOC and PT 
• 
TEAEs by SOC, PT, and worst severity grade 
• 
TEAEs by SOC, PT, and highest relationship (Related, Not Related), for Part C the 
highest relationship to ALKS and Pembrolizumab will be summarized in separate 
tables 
• 
ALKS 4230-related TEAEs by SOC and PT 
• 
Pembrolizumab-related TEAEs by SOC and PT 
• 
Serious TEAEs by SOC and PT 
• 
Treatment-related Serious TEAEs by SOC and PT 
• 
Grade 3 or higher related TEAEs by SOC and PT 
• 
TEAE leading to treatment discontinuation by SOC and PT 
• 
TEAE leading to dose reduction by SOC and PT 
• 
TEAE leading to dose interruption by SOC and PT 
• 
Treatment-related TEAE leading to dose interruption 
• 
TEAEs leading to study discontinuation by SOC and PT 


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• 
Related TEAEs leading to study discontinuation by SOC and PT 
• 
TEAEs meeting DLT leading to study discontinuation by SOC and PT 
The tables will be sorted by overall SOC alphabetically and then, within a SOC, by overall 
descending frequency of PT based on the subject count for the overall column.  
5 PTs including Neutrophil count decreased, Haemoglobin decreased, Platelet count 
decreased, Supraventricular tachycardia, and Lymphocyte count decreased will be 
grouped into new PTs as Neutropenia, Anaemia, Thrombocytopenia, Supraventricular 
extrasystoles, and Lymphopenia respectively. The new grouped SOCs will be Cardiac 
disorders for the original PT of Supraventricular tachycardia, and Blood and lymphatic 
system disorders for the rest of 4 original PTs. 
For summaries by SOC, PT, and intensity, subject is counted only once at the highest 
grade for which the event occurred in the SOC and the highest grade for each unique PT 
within that SOC.  
In addition, AEs reported post 30 days of safety follow-up period may be summarized by 
SOC and PT and/or listed separately. 
The original date and time will be shown on all listings of AEs. Listings will be provided 
for all TEAEs, AEs resulting in death, serious TEAEs, AESIs, DLTs and AEs leading to dose 
reduction, dose interruption and discontinuation.  
9.4. 
LABORATORY EVALUATIONS 
Clinical laboratory data are collected at the time points specified in study procedures and 
flow chart. The assessments are presented in the table on next page. 
 
 


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Hematology 
Biochemistry 
Urinalysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cell count 
• 
Total and differential 
(absolute) white blood 
cell count 
• 
Platelets 
General Chemistry 
• 
Albumin 
• 
Bicarbonate 
• 
Calcium 
• 
Chloride 
• 
Creatine phosphokinase 
• 
Glucose 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
Liver Function Tests 
• 
Alanine transferase 
• 
Alkaline phosphatase 
• 
Aspartate transferase 
• 
Lactic dehydrogenase 
• 
Total bilirubin 
Renal Function Tests 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Thyroid Test 
• 
Thyroid-stimulating 
hormone 
• 
Serum Tumor Marker 
• 
CA125 (ovarian 
cancer subjects only) 
• 
CA19-9 (gastric and 
pancreatic cancer 
subjects only) 
• 
PSA (prostate cancer 
subjects only) 
• 
CEA (colorectal 
cancer subjects only) 
• 
Bilirubin 
• 
Color and appearance 
• 
Glucose 
• 
Ketones 
• 
Leukocytes 
• 
Nitrite 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are 
abnormal. Microscopic 
examination is not needed if 
urinalysis is abnormal for 
bilirubin, glucose, or 
ketones. 
Coagulation 
• 
International normalized 
ratio 
• 
Partial thromboplastin 
time / Activated partial 
thromboplastin time 
Microbiology (as Applicable) 
• 
Blood 
• 
Urine 
• 
Other 
 


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A serum or urine pregnancy test will be administered to all women of childbearing 
potential. At the screening visit, results must be negative for the subject to be eligible 
for the study.  
Separate analysis table for CA125 for ovarian pts will be displayed. 
In addition, the hematology, coagulation, and chemistry laboratory parameters will be 
graded according to NCI CTCAE (version 5.0 or higher) where applicable.  
Subjects who meet the potentially clinically significant (PCS) criteria in selected lab 
parameters will be summarized by treatment cohort, the PCS is defined as Grade 3 or 
above per CTCAE. 
Lab shift table of CTCAE grade (1 to 5) will be summarized from baseline grade to 
minimum, maximum, and final grade.  
Number of subjects who meet the following liver function test criteria will be 
summarized and corresponding listing will be presented: 
 
• 
An elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
laboratory value that is ≥3× the upper limit of normal (ULN) and an elevated 
total bilirubin laboratory value that is ≥2× ULN and an alkaline phosphatase 
laboratory value that is <2× ULN within 3 days. 
 
The corresponding listing will present all AST, ALT, total bilirubin, and alkaline 
phosphatase laboratory data for any subject meeting the aforementioned criteria at 
least one time. 
Listings will be provided for the hematology, coagulation, chemistry, urinalysis, and 
pregnancy tests results.  
9.5. 
VITAL SIGNS  
Vital signs assessments include respiratory rate, temperature, blood pressure, body 
weight, and heart rate.  
The vital signs assessments will be graded according to NCI CTCAE (version 5.0 or higher) 
where applicable.  
Subjects who meet the potentially clinically significant (PCS) criteria in vital sign will be 
summarized by treatment cohort, the PCS is defined as Grade 3 or above per CTCAE. 
Vital signs shift table of CTCAE grade (1 to 5) will be summarized from baseline grade to 
minimum, maximum, and final grade. 


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9.6. 
ECG  
The standard 12-lead ECGs will be performed in triplicate 5 minutes apart at all time 
points outlined in the protocol. The mean value will be used for summary purposes. 
The QTcF Intervals fulfilling grade 3 or above per CTCAE will be tabulated separately.  
Subjects who meet the potentially clinically significant (PCS) criteria in the QTcF will be 
summarized by treatment cohort, the PCS is defined as QTcF >=501 msec or >60 msec 
change from baseline.  
The QTcF shift table of CTCAE grade (1 to 5) will be summarized from baseline grade to 
minimum, maximum, and final grade. 
9.7. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS 
The ECOG performance status assesses the subjects’ activity status and will be assessed 
at the time points specified in Table 3, Table 4, Table 5, Table 6, and Table 7. Possible 
scores are 0 to 5. Descriptions of activity status are presented in Table 12. The data will 
be listed. 
Table 12: Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0  
Fully active, able to carry on all predisease 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. 
9.8. 
PHYSICAL EXAMINATION 
A full physical examination will be performed at screening and end-of–treatment visits. If 
possible, a brief physical examination focused on areas of disease or AE will be assessed 
at Day 1 of each cycle. These data will be available for reference. 


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10. 
INTERIM ANALYSES 
No formal interim analysis is planned with respect to stopping the study early or for lack 
of antitumor activity purposes. Interim data cuts will be conducted to support abstract 
submissions, conference presentations, and/or manuscript(s).  
Responses in each N1 stage will be assessed to determine whether progression to the N2 
stage is warranted, based on criteria defined in Section 3.6. 


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11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
 
Durable response rate is listed as secondary endpoint but no summaries are planned. 
Analysis based on irRC and iRECIST will not be performed as the iRECIST was implemented 
during the middle of the study conduct to replace irRC. The sites have not consistently 
record the iRECIST data which could provide misleading information.  
The protocol stated that the PFS analysis would be only performed for Part B and Part C 
(Cohorts 5-7). The additional PFS analysis in ovarian patients from the PD-L1 unapproved 
cohort will be conducted as ovarian is identified as one of tumor types to advance further 
clinical development in Nemvaleukin in combination with Pembrolizumab. 
 


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12. 
REFERENCE LIST 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009;45(2):228-47. 
Gough K, Hutchinson M, Keene O, et al. Assessment of Dose Proportionality: Report from 
the Statisticians in The Pharmaceutical Industry/Pharmacokinetics UK joint working 
party. Drug Inf J. 1995; 29(3):1039-1048. 
Hummel J, McKendrick S, Brindley C and French, R. Exploratory assessment of dose 
proportionality: review of current approaches and proposal for a practical criterion. 
Pharmaceut. Statist. 2009;8(1):38-49. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartate Guideline: Nonclinical 
evaluation 
for 
anticancer 
pharmaceuticals. 
S9. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S9/St
ep4/S9_Step4_Guideline.pdf. 
Published October 29, 2009. Accessed 01 February 2016. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982:5(6):649-55. 
Smith BP, Vandenhende FR, DeSante KA  et al. Confidence interval criteria for assessment 
of dose proportionality. Pharm Res. 2000; 17(10):1278-1283. 
US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. Published 28 May 2009 (v4.03 14 June 2010). Accessed 
01 February 2016. 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res. 2009;15(23):7412-20. 
 


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13. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), statistical analyses, and non-PK parameter related 
derivations will be generated using SAS® for Windows, Release 9.4 (SAS® Institute Inc., 
Cary, NC, USA). Computer-generated table, listing, and figure outputs will adhere to the 
following specifications below. 
PK parameters will be derived using Phoenix WinNonlin ver 6.4 (Certara, Princeton, NJ, 
USA) by Alkermes who will also be responsible for quality control of the derived 
parameters. 
13.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) E3 guidance.  
13.2. 
TABLE, LISTING, AND FIGURE FORMAT 
13.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8.  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they are 


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appropriate to help display math symbols (eg, μ). Certain subscripts and superscripts 
(eg, cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
13.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Alkermes, Inc.  
Protocol ALK4230-A101 
• 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (ie, the page number 
should appear sequentially as page n of N, where N is the total number of pages in 
the table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 
13.2.3. 
Display Titles 
• 
The title will be centered. The analysis set will be identified on the line immediately 
following the title. The title and table designation will be single spaced. A solid line 
spanning the margins will separate the display titles from the column headers. There 
will be 1 blank line between the last title and the solid line as per the example below. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
_______________________________ 
 
13.2.4. 
Column Headers 
• 
Column headings will be displayed immediately below the solid line described above 
in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by columns for cohorts and total column (if applicable).  
• 
For numeric variables, include “unit” in column or row heading when appropriate. 


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• 
Analysis set sizes will be presented for each cohort in the column heading as (N=xx) 
(or in the row headings if applicable). This is distinct from the ‘n’ used for the 
descriptive statistics representing the number of non-missing subjects in the analysis 
set. 
• 
The order of cohorts in the Part A tables and listings will be by the order of dose 
escalation, as dose level: 0.1 μg/kg, 0.3 μg/kg, 1 μg/kg, 3 μg/kg, 6 μg/kg, 10 μg/kg, 
15 μg/kg, overall (if applicable). The order of cohorts in the Part B tables and listings 
will be: Melanoma, RCC, overall (if applicable). The order of cohorts in the Part C 
tables and listings will be: PD-1 unapproved tumor types, PD-1 approved tumor types 
(PD-1/L1 pretreated), PD-1 approved tumor types (PD-1/L1 treatment naïve), 
Rollover, overall (if applicable). 
13.2.5. 
Body of the Data Display 
13.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (eg, counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
13.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for all 
cohorts in a given category that is between the minimum and maximum level for that 
parameter. For example, the frequency distribution for symptom severity would 
appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
• 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 subject 
represented in 1 or more groups should be included. 


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• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• 
Unless otherwise specified, the estimated mean and median for a set of values should 
be printed out to 1 more significant digit than the original values, and standard 
deviations should be printed out to 2 more significant digits than the original values. 
The minimum and maximum should report the same significant digits as the original 
values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999.  
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise noted, 
for all percentages, the number of subjects in the analysis set for the cohort who have 
an observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100%, without any 
decimal places.  
• 
All tabular displays of AE data should be presented by SOC with the highest occurrence 
in the Overall group in decreasing order, assuming all terms are coded. Within SOC, 
AEs should be displayed in decreasing order of preferred term. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically.  
• 
Tabular display of data for concomitant medications should be presented by ATC4 
Code with the highest occurrence in the Overall group in decreasing order, assuming 
all terms are coded. Within the ATC4 drug class, concomitant medications should be 
displayed in decreasing order of Preferred Term. If medications for more than 1 term 
are identical, they should then be sorted alphabetically.  
• 
Tabular display of data for medical history should be presented by the medical history 
category with the highest occurrence in the Overall group in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted alphabetically. 
• 
Missing descriptive statistics or p-values which cannot be estimated should be 
reported as “-”. 


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• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant cohort (or overall) for the analysis set presented. 
However, careful consideration is required in many instances due to the complicated 
nature of selecting the denominator, usually the appropriate number of subjects 
exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page. The overall summary statistics for the subheading should only be 
output on the first relevant page. 
13.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of cohorts as above, subject number, 
visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with a 
corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS 
format (e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as 
part of the study. 
• 
Units will be included where available. 
13.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., the mean change from Baseline) values will be displayed on the 
Y-axis. 
13.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  


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• 
All footnotes will be left justified with single-line spacing immediately below the solid 
line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be used 
to display footnotes, and only those essential to comprehension of the data will be 
repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program: myprogram.sas       Listing source: 16.x.y.z’). 


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14. 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary tables, 
data listings, figures or statistical analyses. An overview of the development of programs 
is detailed in Syneos Health SOP Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Quality Deliveries (SDTM, 
ADaM, TLF) (3908) describes the quality control procedures that are performed for all SAS 
programs and output. Quality control is defined here as the operational techniques and 
activities undertaken to verify that the SAS programs produce the output by checking for 
their logic, efficiency and commenting and by review of the produced output. 
Syneos Health SOP Pharmacokinetic and Related Data Analyses and Reporting (03.016) 
describes the procedure for the generation and reporting of PK and pharmacodynamics 
data. 
 


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15. 
MOCK SHELLS OF TABLES, FIGURES, AND LISTINGS 
Templates of the TLFs are provided in a separate document.