Clinical trial NCT04144517
Conditions: Squamous Cell Carcinoma of Head and Neck
Keywords: Alkermes IL-2 Interleukin-2 Oncology Immuno-oncology Cytokine Immunotherapy ALKS 4230 Pembrolizumab Keytruda PD-L1 Solid Tumors
Sponsor: Mural Oncology, Inc
Start date: 2020-02-05; Completion date: 2022-01-07
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study was to estimate the response rate to ALKS 4230 in combination with pembrolizumab in patients with HNSCC who had previously received anti-PD-(L)1 therapy but who had not achieved a CR.

Detailed description:

Arms: arm 1: Participants with current stable disease (SD) or partial response (PR) (Cohorts 1 and 2) who were not progressing or further demonstrating reductions in tumor size were to receive nemvaleukin alfa 3 microgram per kilogram (mcg/kg), intravenous (IV) infusion, daily from Days 1 to 5 of the first week of each 3-week treatment cycle in combination with pembrolizumab 200 milligram (mg), IV infusion, once, every three weeks (Q3W) on Day 1 of each 21-day cycle until confirmed progression, unacceptable toxicity or met other criteria for discontinuation. arm 2: Participants with progressive disease (PD) (Cohorts 3 and 4) received nemvaleukin alfa 3 mcg/kg, IV infusion, daily from Days 1 to 5 of the first week of each 3-week treatment cycle in combination with pembrolizumab 200 mg, IV infusion, once, Q3W on Day 1 of each 21-day cycle until confirmed progression, unacceptable toxicity or met other criteria for discontinuation.
Interventions: intervention 1: Nemvaleukin Alfa intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Nemvaleukin alfa IV infusion. intervention 2: Pembrolizumab IV infusion.

Protocol documents:
Prot_000.pdf: 
 
 
 
1. 
TITLE PAGE 
 
 
CLINICAL STUDY PROTOCOL 
ION-01-ALKS 4230 
 
Study Title: 
A Phase 2 Study of ALKS 4230 in Combination With Anti-PD-1 
(Pembrolizumab) in Patients With Advanced or Recurrent Head 
and Neck Squamous Cell Cancer Currently on Treatment With 
Anti-PD-(L)1 Without Having Achieved a Complete Remission 
Document Date: 29 Oct 2018 
Sponsor: 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451-1420 
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. 
 
 
 
 
 


 
 
Alkermes, Inc. 
Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Contact Information 
Alkermes Medical Monitor 
 MD 
 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451-1420 
 
ION Medical Monitor 
, 
MD 
 
1100 Eastlake Ave. E 
Seattle, WA 98109 
+1 (206) 667-4141 
Lead Investigator 
, MD 
 
825 Eastlake Ave. E 
Seattle, WA 98109 
 
Co-lead Investigator 
, MD 
 
9500 Euclid Ave. 
Cleveland, OH 44195 
 
ION Laboratory Director 
 
 
1100 Eastlake Ave. E 
Seattle, WA 98109 
 
24-Hour Emergency Contact 
, PhD 
 
1100 Eastlake Ave. E 
Seattle, WA 98109 
 
Global Safety Officer 
MD, PhD 
 
 
Alkermes, Inc. 
852 Winter Street 
Waltham, MA 02451-1420 
 
Abbreviation: ION=Immune Oncology Network 
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: Alkermes, Inc. 
Name of Investigational Product: ALKS 4230 
Name of Active Ingredients: ALKS 4230 and pembrolizumab 
Title of Study: A Phase 2 Study of ALKS 4230 in Combination With Anti-PD-1 (Pembrolizumab) in 
Patients With Advanced or Recurrent Head and Neck Squamous Cell Cancer Currently on Treatment 
With Anti-PD-(L)1 Without Having Achieved a Complete Remission 
Investigators: 
 (Coordinating Investigator), other investigators at selected study sites 
Study Period (Years): Approximately 2 years 
Estimated date first patient enrolled: March 2019 
Estimated date last patient completed: February 2021 
Phase of Development: 2 
 
Objectives:  
Primary: 
• 
To estimate the response rate to ALKS 4230 in combination with pembrolizumab in patients 
with squamous cell carcinoma of the head and neck (HNSCC) who have previously received 
anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed cell death ligand-1 
(anti-PD-L1) (henceforth referred to as PD-[L]1) therapy but who have not achieved a 
complete remission (CR). The primary objective will be assessed for the following 2 groups:  
− 
Group 1: Patients with stable disease (SD), defined as ≥12 weeks of SD per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, or patients with partial 
response (PR) with no further reduction in tumor size or response (ie, PR and not 
improving further) for ≥8 weeks on prior anti-PD-(L)1 therapy  
− 
Group 2: Patients with progressive disease (PD) with no prior response to anti-PD-(L)1 
therapy after ≥8 weeks on anti-PD-1 therapy or patients currently with PD after prior 
achievement of a best response of SD or PR and after ≥8 weeks on anti-PD-(L)1 therapy 
Secondary: 
• 
To evaluate the duration of response (DOR), progression-free survival (PFS), time to 
progression (TTP), and overall survival (OS) of patients with advanced or recurrent HNSCC 
receiving pembrolizumab plus ALKS 4230 
• 
To evaluate the safety and tolerability of pembrolizumab plus ALKS 4230 
Exploratory: 
• 
To evaluate whether assessment of pretreatment biopsies from patients who have failed to 
achieve a CR on therapy with anti-PD-(L)1 can identify a subset of patients who are likely 
to respond to the addition of ALKS 4230 
• 
To evaluate whether a second biopsy, 
, can identify changes 
in tumors that will predict response or failure to the addition of ALKS 4230 
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
• 
 
Methodology: This is a multi-center, Phase 2, open-label therapy study to assess the antitumor efficacy 
of ALKS 4230 in combination with pembrolizumab in patients with advanced, recurrent and/or 
metastatic HNSCC on treatment with an anti-PD-(L)1 antibody without having achieved a CR.  
Study Design Schematic 1 
 
Pembrolizumab regimen: 200 mg once Q3W by IV infusion 
ALKS 4230 regimen: 3 µg/kg, given daily on 5 consecutive days on Days 1 through 5 of the first week of each 
3-week treatment cycle. 
Abbreviations: CR=complete remission; HNSCC=squamous cell carcinoma of the head and neck; PD-
(L)1=programmed cell death ligand-1; PR=partial response; SD=stable disease; Q3W=every 3 weeks 
For analysis, patients will be placed into 1 of the 4 cohorts based on their disease status as assessed at 
screening: 
• 
Cohort 1: SD; defined as ≥12 weeks of SD per RECIST v1.1 criteria 
• 
Cohort 2: PR with no further reduction in tumor size or response for ≥8 weeks (ie, PR and 
not improving further)  
• 
Cohort 3: PD with no prior response to anti-PD-(L)1 therapy after ≥8 weeks on anti-PD-
(L)1; or  
• 
Cohort 4: Progressive disease after prior achievement of a best response of SD or PR and 
after ≥8 weeks on anti-PD-(L)1 therapy 
All patients will be administered the combination of ALKS 4230 and pembrolizumab. For analysis, 
patients in the 4 cohorts will be combined into 2 groups:  
• 
Group 1 will consist of all patients with current SD or PR (Cohorts 1 and 2) who are not 
progressing or further demonstrating reductions in tumor size.  
• 
Group 2 will consist of patients with PD (Cohorts 3 and 4). 
Patients in both groups (or all cohorts) will receive pembrolizumab 200 mg once every 3 weeks (Q3W) 
by intravenous (IV) infusion (Keytruda USPI) and ALKS 4230 3 µg/kg, given daily on 5 consecutive 
days on Days 1 through 5 of the first week of each 3-week treatment cycle.  
Patients will have a pretreatment biopsy within 6 weeks of Cycle (C) 1, Week 1, Day (D) 1 and a 
post-treatment (second) biopsy at C1D12, or any time from C1D8 through C1D19, to assess whether the 
addition of ALKS 4230 to the treatment regimen alters the tumor microenvironment and what changes 
on therapy (immunopharmacodynamics) predispose to responses to the combination.  
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
The study plans to enroll 
 patients in total 
. The number of patients 
enrolled into each cohort within each group will be determined at the time of enrollment, based on the 
patient’s response to previous treatment. It will be at the discretion of Alkermes and the Immune 
Oncology Network (ION) to expand a particular cohort of interest.  
Study Design Schematic 2 
Abbreviations: IV=intravenous; Q3W=every 3 weeks. 
Dose delays and modifications for adverse events (AEs) related to the ALKS 4230 + pembrolizumab 
combination regimen are described in the protocol. After recovery from an AE that meets dose hold 
criteria, the patient may resume dosing at full dose of pembrolizumab and full or reduced dose of ALKS 
4230 in subsequent cycles, with consultation from the ION and Alkermes Medical Monitors, or may 
discontinue from the study.
 
Patients with tumors who respond to treatment will continue until the following:  
• 
Confirmed progression occurs (upon agreement with the ION and Alkermes Medical Monitors, 
patients tolerating therapy and receiving clinical benefit may be allowed to stay on study for up 
to 1 year)  
• 
Until unacceptable toxicity occurs 
• 
Other criteria for discontinuation occur 
Safety and tolerability will be assessed and reported using standard Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 criteria. Safety will be monitored by the study Principal Investigator 
(PI), participating site PIs, the ION Coordinating Center PI and staff, and representatives from 
Alkermes. 
Number of Patients Planned: 
 
Main Criteria for Inclusion:  
Inclusion Criteria: 
Each patient must meet all of the following inclusion criteria to be qualified to participate in this study: 
1. Is ≥18 years of age. 
2. Is willing and able to provide informed consent. 
3. Is willing and able to follow the study procedures as outlined in the protocol. 
4. Must have a histologically or cytopathologically confirmed diagnosis of squamous cell 
carcinoma of the head and neck region that is locally advanced or recurrent and no longer 
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
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amenable to local surgical or radiation therapy and/or with evidence of metastatic disease. Both 
HPV-positive and -negative patients will be included. 
5. Must have had prior PD-1:PD-L1 inhibition therapy with anti-PD-(L)1 therapy as the most 
recent systemic therapy with 
a. (Group 1, Cohort 1) current SD (for ≥12 weeks by RECIST] criteria v1.1) or  
b. (Group 1, Cohort 2) current PR with no further reduction in tumor size or response for 
≥8 weeks (ie, PR and not further improving 
c. (Group 2, Cohort 3) current PD with no prior response to anti-PD-(L)1 therapy after 
≥8 weeks on anti-PD-(L)1 or  
d. (Group 2, Cohort 4) current PD after prior achievement of a best response of SD or PR and 
after ≥8 weeks on anti-PD-(L)1 therapy. 
Some minimal intervening localized palliative radiotherapy or ablation therapy may be 
allowed upon review and agreement by the ION and Alkermes Medical Monitors. 
6. Must have disease that is measurable by RECIST v1.1 criteria as determined by the treating 
physician and not confounded by prior treatment such as radiation. Patients with only 1 site of 
disease must be able to provide adequate tissue samples at the time of biopsy that will not affect 
the tumor size per RECIST v1.1 criteria.  
7. Patients who have received standard or investigational anti-PD-(L)1 agents as the most recent 
systemic therapy must wait at least 3 weeks (with the exception of an anti-PD-[L]1 inhibitor that 
is dosed every 2 weeks and in consultation with the ION and Alkermes Medical Monitors, in 
which case patients must wait at least 2 weeks) before enrollment into the study or 4 weeks if 
the half-life of the investigational agent is not known. Patients who have received standard or 
investigational agents other than anti-PD-(L)1 agents (including agents as part of a combination 
regimen with an anti-PD-[L]1 agent) must wait 8 weeks before enrollment into the study, unless 
discussed with and approved by the ION and Alkermes Medical Monitors on an individual 
basis. 
8. Patients must be willing to provide tumor tissue adequate for biomarker correlative studies at the 
time points specified in the protocol. 
9. Patients should have readily accessible tumor for biopsy pre- and post-pembrolizumab and 
ALKS 4230 combination regimen. Biopsy should be excisional, incisional, or core needle and 
large enough to show tissue architecture. 
10. Have a performance status of ≤2 on the Eastern Cooperative Oncology Group Performance 
Scale. 
11. Demonstrate adequate organ function. All screening laboratories should be performed within 
10 days of treatment initiation. 
12. Female patients of childbearing potential should have a negative urine or serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.  
13. Is willing to abide by the contraception requirements for the duration of the study. Additional 
details pertaining to contraception requirements are detailed in the protocol. 
 
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
Exclusion Criteria: 
Each patient must not have any of the following conditions to be qualified to participate in this study: 
1. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (inhaled or topical 
steroids are allowable) or any other form of immunosuppressive therapy within 7 days prior to 
the first dose of study drug. 
2. Has active tuberculosis (TB; Bacillus tuberculosis). 
3. Has hypersensitivity to pembrolizumab, ALKS 4230, or any of their excipients. 
4. Has prior Grade ≥3 immune-related toxicities requiring systemic immunosuppressant treatment 
that were attributable or possibly attributable to PD-1 immune checkpoint blockade. Has 
toxicities deemed reversible from prior therapy, including anti-PD-1, that have not recovered to 
baseline or Grade ≤1. Patients with persistent Grade ≤2 neuropathy are an exception to this 
criterion and may qualify for the study. 
a. Note: If patient received major surgery, the patient must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.  
5. Has had a prior dose of anti-PD-(L)1 therapy within 3 weeks of Study Day 1, with the exception 
of an anti-PD-(L)1 inhibitor that is dosed every 2 weeks and in consultation with the ION and 
Alkermes Medical Monitors. 
6. Has a known history of additional malignancy within 2 years or current additional malignancy 
that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the 
skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, in 
situ cervical cancer, or treated prostate cancer with a prostate-specific antigen value of 
<0.01 ng/mL. 
7. Has known active central nervous system metastases and/or carcinomatous meningitis. Patients 
with previously treated brain metastases may participate, provided that they are stable (without 
evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug and 
any neurologic symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to study drug. This exception 
does not include carcinomatous meningitis, which is excluded regardless of clinical stability.  
8. Has known history of, or any evidence of, non-infectious interstitial pneumonitis that required 
steroids or current pneumonitis, or oxygen requirement for any reason in the past 28 days. 
9. Has an active major infection requiring systemic therapy within 1 week of starting study drug. 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the patient’s participation for the full duration of 
the study, or is not in the best interest of the patient to participate, in the opinion of the treating 
Investigator.  
11. Has known psychiatric or substance abuse disorders or a social situation that would interfere 
with cooperation with the requirements of the study. 
12. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the Screening Visit through 120 days after the last dose of 
study drug. 
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
13. Known active infection with hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or 
hepatitis C (hepatitis C virus HCV RNA [qualitative]) detected.  
14. Has any finding that, in the view of the Investigator, would compromise the safety of the patient 
or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements. 
15. Is Investigator-site personnel, an immediate family of the Investigator-site personnel, employed 
by Alkermes or ION, or an immediate family member of an Alkermes or ION employee. 
16. If, in the opinion of the Investigator (and/or Sponsor), the patient is unsuitable for enrollment in 
the study. 
17. Has significant known cardiovascular impairment (New York Heart Association Congestive 
Heart Failure >Grade 2, unstable angina, myocardial infarction within the previous 6 months 
prior to the first dose of investigational drug, or existing serious cardiac arrhythmia). 
18. Has chronic or acute gastrointestinal disorders resulting in diarrhea of any severity grade; patient 
is using chronic anti-diarrheal supportive care (more than 3 days/week) to control diarrhea in the 
28 days prior to the first dose of investigational drug. 
19. Has known cirrhosis diagnosed with Child-Pugh Class A or higher liver disease. 
Investigational Product, Dosage, Duration, and Mode of Administration:
Reconstituted ALKS 4230 is administered via a 30-minute IV infusion once daily for 5 consecutive days 
during the first week of each treatment cycle.  
 
Pembrolizumab is to be administered as an IV infusion over 30 minutes in a dose of 200 mg Q3W, for 
up to 1 year for as long as patients are deriving clinical benefit (ie, objective response or SD) and 
tolerating therapy well.  
Reference Therapy, Dosage, Duration, and Mode of Administration: None 
Duration of Study: This study consists of a 28-day screening period, treatment period, and 30-day 
post-treatment follow-up. The treatment period consists of at least five 3-week cycles that can repeat for 
up to 1 year.  
Efficacy Endpoints: The primary efficacy endpoint is the rate of new or improved antitumor response 
after the addition of ALKS 4230 treatment in patients receiving ongoing anti-PD-1 therapy but who have 
not achieved a CR. 
The secondary efficacy endpoints in this study include:  
1. Duration of response, progression-free survival, time to progression, rate of non-progression at 
6 months, and OS 
2. Antitumor response rate of subsets of patients based on disease status (PR, SD, or PD) at 
 
 
 
 
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Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
screening 
3. Antitumor activity as measured by radiological assessment compared to screening 
Safety Assessments: 
• 
Adverse events 
• 
Physical examination and electrocardiogram findings 
• 
Vital signs (ie, blood pressure, pulse, respiratory rate, and body temperature)  
• 
Clinical laboratory parameters (ie, complete blood count with differential, complete serum 
chemistry, and urinalysis) 
Statistical Methods: For all applicable parameters, descriptive statistics will be provided. 
Efficacy: Response to treatment will be evaluated using both Response Evaluation Criteria in Solid 
Tumors v1.1 and immune-related response criteria. For patients with objectively measurable disease, 
response to therapy, DOR, PFS, and OS will be calculated.  
Primary efficacy endpoint will be evaluated in the Efficacy Evaluable population (all patients who 
received at least 1 dose of both study drugs) for each group separately and overall. The rate of objective 
improvement after continued anti-PD-1 therapy with ALKS 4230 will be summarized by groups (Group 
1 and Group 2) and overall population with descriptive statistics. The analysis of objective response 
using an exact binomial test will be conducted separately for each group and overall; the 95% 
confidence interval will be reported. 
Secondary efficacy endpoints will be evaluated in the Efficacy Evaluable population (Group 1 and 
Group 2). 
DOR and TTP will be calculated and summarized by group and overall. PFS and OS curves will be 
plotted by group and overall using the Kaplan-Meier (KM) approach. The median survival time (if 
applicable) and its 95% CI for PFS and OS will be reported. The PFS and OS rates at 6 and 12 months 
will be estimated using the KM approach.  
The objective response rate will be summarized for each of the 4 cohorts. 
The percentage change from baseline in target lesions will be summarized by groups and overall. 
Safety: The incidence of TEAEs will be summarized for the Safety Population, defined as all patients 
who received at least 1 dose of investigational combination, each group and overall, by severity, and by 
relationship to study drug as assessed by the Investigator. Similar tables will be prepared for SAEs, 
TEAEs leading to discontinuation, as well as additional categories of AEs as defined in the SAP. 
Adverse event severity will be graded according to the CTCAE v5.0 and terms recorded on the CRFs 
will be mapped to preferred terms using MedDRA version 21. 
Results of clinical laboratory tests will be summarized by visit for the absolute value and for change 
from baseline. Tables showing the shift from baseline will also be presented. ECG findings will be 
listed. 
Concomitant medications will be categorized and presented using the World Health Organization 
Anatomical Therapeutic Chemical drug classification system. 
Sample Size Considerations: This study plans to enroll 
evaluable patients in treatment 
Groups 1 and 2, 
 
 
 
 
 
 
 
 
 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Disease Overview .......................................................................................................19 
5.2. 
Study Rationale ...........................................................................................................20 
5.3. 
Dose Selection ............................................................................................................22 
5.3.1. 
Pembrolizumab ...........................................................................................................22 
5.3.2. 
ALKS 4230 .................................................................................................................22 
6. 
STUDY OBJECTIVES ..............................................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
6.2. 
Secondary Objectives .................................................................................................23 
6.3. 
Exploratory Objectives ...............................................................................................23 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................24 
7.1. 
Patient Inclusion Criteria ............................................................................................24 
7.2. 
Patient Exclusion Criteria ...........................................................................................26 
7.3. 
Patient Withdrawal and Discontinuation ....................................................................27 
7.3.1. 
Discontinuation of Study Drug After Complete Remission .......................................28 
7.4. 
Replacement of Patients .............................................................................................28 
8. 
STUDY DESIGN .......................................................................................................30 
8.1. 
Overall Study Design and Plan ...................................................................................30 
8.2. 
Schedule of Assessments ............................................................................................32 
8.3. 
Study Procedures Descriptions ...................................................................................40 
8.3.1. 
Informed Consent .......................................................................................................40 
8.3.2. 
Eligibility Review .......................................................................................................40 
8.3.3. 
Demographics and Medical History ...........................................................................40 
8.3.4. 
Prior and Concomitant Medication Review ...............................................................40 
 
 
 
 
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8.3.5. 
Infusion-Type Reactions .............................................................................................40 
8.3.6. 
Vital Signs and Weight ...............................................................................................41 
8.3.7. 
Physical Examination .................................................................................................41 
8.3.8. 
12-Lead Electrocardiogram ........................................................................................41 
8.3.9. 
Eastern Cooperative Oncology Group Performance Status ........................................41 
8.3.10. 
Tumor Imaging and Assessment of Disease ...............................................................41 
8.3.10.1. 
Definitions ..................................................................................................................44 
8.3.10.2. 
Disease Parameters .....................................................................................................44 
8.3.10.3. 
Methods for Evaluation of Measurable Disease .........................................................45 
8.3.10.4. 
Response Criteria ........................................................................................................46 
8.3.10.5. 
Evaluation of Best Overall Response .........................................................................47 
8.3.10.6. 
Duration of Response .................................................................................................48 
8.3.11. 
Laboratory Assessments .............................................................................................48 
8.3.11.1. 
Pregnancy Testing ......................................................................................................50 
8.3.11.2. 
Serology Testing .........................................................................................................50 
8.3.12. 
Laboratory Correlative Studies ...................................................................................50 
8.3.12.1. 
Correlative Studies With Biopsies ..............................................................................50 
8.3.12.2. 
Correlative Studies with Blood Draws .......................................................................51 
8.3.12.3. 
Microbiome Analysis ..................................................................................................53 
8.3.13. 
Drug Dispensation and Reconciliation .......................................................................54 
8.3.13.1. 
Collection of Specimens .............................................................................................54 
8.3.13.2. 
Handling and Shipping of Specimens.........................................................................54 
8.3.14. 
Randomization ............................................................................................................55 
8.3.15. 
Adverse Event Monitoring .........................................................................................55 
8.4. 
Study Requirements and Restrictions .........................................................................55 
8.4.1. 
Contraception and Pregnancy .....................................................................................55 
8.4.2. 
Prohibited Medications and Supportive Care .............................................................56 
9. 
TREATMENT OF PATIENTS ..................................................................................59 
9.1. 
Study Drug Dose and Administration .........................................................................59 
9.1.1. 
ALKS 4230 .................................................................................................................59 
9.1.2. 
Pembrolizumab ...........................................................................................................59 
9.2. 
Treatment Adherence ..................................................................................................60 
9.3. 
Randomization/Method of Assigning Patients to Treatment ......................................60 
 
 
 
 
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9.4. 
Blinding ......................................................................................................................60 
9.5. 
Study Drug Dose Delays, Interruptions, and Stopping Rules ....................................60 
9.5.1. 
Dose Delays ................................................................................................................60 
9.5.2. 
Dose Interruptions and Stopping Rules ......................................................................60 
9.5.3. 
Dose Modifications .....................................................................................................62 
9.5.4. 
Dose Delays and Modification Guidelines for Events Considered Related to 
Study Drug ..................................................................................................................63 
9.5.4.1. 
Events Considered Related to ALKS 4230 ................................................................63 
9.5.4.2. 
Events Considered Related to Pembrolizumab ...........................................................66 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................67 
10.1. 
Study Drug ..................................................................................................................67 
10.1.1. 
ALKS 4230 .................................................................................................................67 
10.1.2. 
Pembrolizumab ...........................................................................................................67 
10.2. 
Packaging and Labeling ..............................................................................................67 
10.2.1. 
ALKS 4230 .................................................................................................................67 
10.2.2. 
Pembrolizumab ...........................................................................................................67 
10.3. 
Storage ........................................................................................................................68 
10.3.1. 
ALKS 4230 .................................................................................................................68 
10.3.2. 
Pembrolizumab ...........................................................................................................68 
10.4. 
Accountability .............................................................................................................68 
10.5. 
Handling and Disposal ................................................................................................68 
11. 
ASSESSMENT OF EFFICACY ................................................................................70 
11.1. 
Primary Efficacy Endpoint .........................................................................................70 
11.2. 
Secondary Efficacy Endpoints ....................................................................................71 
11.3. 
Exploratory Efficacy Endpoints .................................................................................71 
12. 
ASSESSMENT OF SAFETY .....................................................................................73 
12.1. 
Definition of Adverse Event .......................................................................................73 
12.1.1. 
Events of Clinical Interest ..........................................................................................73 
12.2. 
Definition of Serious Adverse Events ........................................................................74 
12.3. 
Relationship to Study Drug ........................................................................................74 
12.3.1. 
Toxicity Management for Immune-related Adverse Events Associated with 
Pembrolizumab ...........................................................................................................75 
12.3.2. 
Toxicity Management for Infusion Reactions Related to Pembrolizumab ................79 
 
 
 
 
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12.4. 
Monitoring and Recording of Adverse Events ...........................................................81 
12.5. 
Reporting of Serious Adverse Events and Pregnancy ................................................82 
12.5.1. 
Protocol-specific Exemptions to Serious Adverse Event Reporting ..........................82 
12.5.2. 
Reporting of Pregnancy Events ..................................................................................83 
13. 
STATISTICS ..............................................................................................................84 
13.1. 
Sample Size Considerations .......................................................................................84 
13.2. 
General Statistical Methodology ................................................................................84 
13.2.1. 
Study Populations .......................................................................................................84 
13.2.1.1. 
Efficacy Evaluable Population ...................................................................................84 
13.2.1.2. 
Safety Population ........................................................................................................85 
13.3. 
Demographics and Baseline Data ...............................................................................85 
13.4. 
Efficacy Analyses .......................................................................................................85 
13.4.1. 
Primary Efficacy Endpoints Analysis .........................................................................85 
13.4.2. 
Secondary Efficacy Analysis ......................................................................................85 
 
85 
13.5. 
Safety and Tolerability Analyses ................................................................................86 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................87 
14.1. 
Study Monitoring ........................................................................................................87 
14.2. 
Audits and Inspections ................................................................................................87 
14.3. 
Institutional Review Board/Independent Ethics Committee ......................................87 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................88 
15.1. 
Case Report Forms .....................................................................................................88 
15.2. 
Confidentiality of Data ...............................................................................................88 
16. 
ETHICAL CONSIDERATIONS................................................................................89 
16.1. 
Ethics Review .............................................................................................................89 
16.2. 
Ethical Conduct of the Study ......................................................................................89 
16.3. 
Written Informed Consent ..........................................................................................89 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................91 
17.1. 
Data Capture ...............................................................................................................91 
17.2. 
Inspection of Records .................................................................................................91 
17.3. 
Retention of Records ..................................................................................................91 
18. 
REFERENCES ...........................................................................................................92 
19. 
APPENDIX A: LABORATORY CORRELATES ....................................................94 
 
 
 
 
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20. 
APPENDIX B: ADDITIONAL INFORMATION FOR MANAGING 
IMMUNE-RELATED PEMBROLIZUMAB TOXICITIES .....................................96 
 
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................2 
Table 2: 
List of Abbreviations and Definition of Terms ..........................................................15 
Table 3: 
Laboratory Values Defining Adequate Organ Function .............................................25 
Table 4: 
Schedule of Assessments and Study Visits ................................................................33 
Table 5: 
Long-term Follow-up Schedule ..................................................................................39 
Table 6: 
Eastern Cooperative Oncology Group Performance Status ........................................41 
Table 7: 
Tumor Imaging/Assessment for Disease Progression ................................................43 
Table 8: 
Best Overall Response for Patients with Measurable Disease (ie, Target 
Disease) .......................................................................................................................47 
Table 9: 
Best Overall Response for Patients with Non-Measurable Disease (ie, 
Non-Target Disease) ...................................................................................................48 
Table 10: Clinical Laboratory Assessments ...............................................................................49 
Table 11: Study Drug Dose Interruptions and Stopping Rules for ALKS 4230 ........................61 
Table 12: Dose Management for Toxicities Related to ALKS 4230 ..........................................64 
Table 13: Adverse Event Causality Guidelines ..........................................................................75 
Table 14: Dose Modification and Toxicity Management for Immune-related Toxicities 
Related to Pembrolizumab ..........................................................................................76 
Table 15: Dose Modification and Toxicity Management for Infusion Reactions Related 
to Pembrolizumab .......................................................................................................80 
Table 16: Laboratory Correlates .................................................................................................94 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic 1 ..........................................................................................32 
Figure 2: 
Study Design Schematic 2 ..........................................................................................32 
 
  
 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
List of Abbreviations and Definition of Terms  
Abbreviation or Term 
Full Form of Definition 
ACTH 
Adrenocorticotropic hormone 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BCG 
Bacillus Calmette-Guérin 
BUN 
Blood urea nitrogen 
C 
Cycle 
CBC 
Complete blood count 
CI 
Confidence interval 
CIML 
Central Immune Monitoring Laboratory 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CR 
Complete remission 
CrCl 
Creatinine clearance 
CRO 
Contract research organization 
CSA 
Clinical Study Agreement 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DKA 
Diabetic ketoacidosis 
DLT 
Dose-limiting toxicities 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
D/C 
Discontinuation 
ECG 
Electrocardiogram 
 
 
 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form of Definition 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
EOT 
End of Treatment 
FDG 
Fluorodeoxyglucose 
FHCRC 
Fred Hutchinson Cancer Research Center 
FIH 
First-in-human 
FNA 
Fine needle aspiration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSCC 
Squamous cell carcinoma of the head and neck 
HPV 
Human papillomavirus 
hsTCRB 
Human T-cell receptor beta chain 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ID 
Identification 
IEC 
Independent ethics committee 
IFN 
Interferon 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IL-2R 
Interleukin-2 receptor 
 
 
 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form of Definition 
INR 
International normalized ratio 
ION 
Immune Oncology Network 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
irRC 
Immune-related response criteria 
IUD 
Intrauterine device 
IV 
Intravenous, intravenously 
Kyn 
Kynurenine 
LDH 
Lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
Mean fluorescence intensity 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK 
Natural killer 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed cell death protein-1 
PD-L1 
Programmed cell death ligand-1 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PR 
Partial response 
PT 
Prothrombin time 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
 
 
 
 
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Table 2: 
List of Abbreviations and Definition of Terms (Continued) 
Abbreviation or Term 
Full Form of Definition 
R 
Receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
rRNA 
Ribosomal ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOP 
Standard operating procedures 
SRC 
Safety Review Committee 
T1DM 
Type 1 diabetes mellitus 
TB 
Tuberculosis 
TCR 
T-cell receptor 
TCRB 
T-cell receptor beta chain 
TEAE 
Treatment-emergent adverse event 
TIL 
Tumor-infiltrating lymphocytes 
TMB 
Tumor mutational burden 
TME 
Tumor microenvironment 
Treg 
Regulatory T cell 
Trp 
Tryptophan 
TSH 
Thyroid-stimulating hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
USP-NF 
United States Pharmacopeia-National Formulary 
WGS 
Whole genome shotgun 
WHO-ATC 
World Health Organization-Anatomical Therapeutic Chemical (drug 
classification system) 
 
 
 
 
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5. 
INTRODUCTION 
5.1. 
Disease Overview 
Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common cancer 
worldwide (SEER database). An estimated 61,000 new cases of HNSCC were diagnosed in 2016 
in the US alone, with approximately 13,000 patients dying of their disease. Despite advances in 
the diagnosis and treatment of this disease, the prognosis for patients with HNSCC remains poor 
(Kamangar et al, 2006; Siegel et al, 2016). Approximately two-thirds of HNSCC cases are 
diagnosed in advanced stages, although metastatic disease at presentation is uncommon (Argiris 
et al, 2008; National Comprehensive Cancer Network 2016; Rothenberg and Ellisen 2012). 
Recurrent and metastatic diseases are often refractory or unable to be treated with further surgery 
and/or radiation therapy (Colevas 2006; Specenier and Vermorken 2008). The 5-year survival 
rate for later-stage disease is estimated to be 50% or less (Gregoire et al, 2010; Lefebvre 2005; 
Rousseau and Badoual 2012). Metastatic and recurrent HNSCC that is no longer amenable to 
local surgical/radiation therapy is associated with a high mortality rate and a median survival of 
6 to 9 months (Lefebvre 2005; Vermorken et al, 2008). First-line therapy with platinum-based 
therapy in combination with 5FU and cetuximab offers some palliation and efficacy but also high 
treatment-related toxicity. For patients with disease progression after first-line therapy, or who 
are platinum intolerant or platinum refractory, the anti-programmed cell death protein-1 (PD-1) 
antibodies, nivolumab and pembrolizumab, have demonstrated substantial palliative benefits 
with durable tumor regressions noted.  
Pembrolizumab is indicated for the treatment of patients with recurrent or metastatic HNSCC 
with disease progression on or after platinum-containing chemotherapy, and this therapy is 
considered standard of care. Pembrolizumab was granted accelerated approval in 2017 based on 
an overall response rate (ORR) of 16% (95% confidence interval [CI]: 11, 22) and a complete 
response rate of 5% in a non-randomized study of 174 patients with recurrent or metastatic 
HNSCC refractory to platinum-containing chemotherapy (Larkins et al, 2017). Patients received 
pembrolizumab 10 mg/kg every 2 weeks (Q2W; n=53) or the now standard regimen of 200 mg 
every 3 weeks (Q3W; n=121) (Keytruda USPI). Among the 28 responding patients, the median 
duration of response (DOR) had not been reached (range 2.4+ to 27.7+ months), and the ORR 
and DOR were similar irrespective of dosage regimen (10 mg/kg Q2W or 200 mg Q3W) or 
human papillomavirus (HPV) status (Keytruda USPI). Subsequently, the efficacy of 
pembrolizumab was demonstrated in a single-arm study of 177 platinum- and cetuximab-
pretreated HNSCC patients who had an ORR of 16% (95% CI: 11, 23) with a median DOR of 
8 months (range 2+ to 12+ months) (Bauml et al, 2017). The open-label randomized Phase 3 
study, Keynote 040, in platinum-pretreated HNSCC patients demonstrated that pembrolizumab 
narrowly failed to improve the primary endpoint of overall survival (OS) compared to the 
Investigator’s choice therapy; the study’s ORR was 14.6% in the pembrolizumab arm vs 10.1% 
with the active comparator (hazard ratio 0.81, one-sided P=0.0204) (Cohen et al, 2017). 
Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 
patients with melanoma or non-small cell lung cancer (NSCLC), with the exception of increased 
incidences of facial edema (10% all Grades; 2.1% Grades 3 to 4) and new or worsening 
hypothyroidism (14.6%) (Larkins et al, 2017; Seiwert et al, 2016). 
 
 
 
 
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ALKS 4230 is an engineered fusion protein composed of a circularly permuted interleukin (IL)-2 
and IL-2 receptor (R; 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 (aldesleukin).  
ALKS 4230 is agonist for IL-2Rβ and the common gamma chains, the two chains that make up 
the intermediate-affinity IL-2R. This is the same receptor complex stimulated by IL-15:IL-15Rα. 
Accordingly, ALKS 4230 functions in a fashion similar to IL-15, in that it activates and expands 
CD8+ T cell and natural killer (NK) cells in preference to other categories of T cells and 
lymphocytes. In early clinical data, both ALKS 4230 and IL-15 function as T-cell growth factors 
that both activate and induce expansion of T cells and NK cells. PD-1 blocking antibodies 
“unleash” T cells, including T cells that can recognize and kill tumor cells. Theoretically, the 
combination of a T-cell growth factor with an agent that “unleashes” T cells should be 
synergistic in patients with T cells capable of recognizing and killing cancer cells. The synergy 
of anti-PD-1 and ALKS 4230 has previously been demonstrated in a murine model. The murine 
ortholog of ALKS 4230 delayed tumor growth in a subcutaneous B16F10 tumor model when 
used as monotherapy and in combination with anti-PD-1 (Losey et al, 2017). This study will test 
whether patients with HNSCC treated with anti-PD-1 therapy (pembrolizumab or nivolumab) 
who have failed to achieve complete remission (CR) can achieve partial or complete tumor 
response by the addition of ALKS 4230 in combination with pembrolizumab.  
5.2. 
Study Rationale 
Although the clinical studies with nivolumab and pembrolizumab have demonstrated antitumor 
activity and established the efficacy, activity, and benefits with anti-PD-1 therapy in the 
recurrent metastatic platinum-experienced HNSCC population, the response rates remain low, 
and the numbers of patients who relapse or fail to achieve CR remain in the high majority of 
85% or more. As patients with HNSCC suffer tremendous morbidity and mortality with this 
disease, and the efficacy of any single-agent chemotherapy remains low with no proven salvage 
options in this population that fails anti PD-1 therapy, there is an exceptionally high unmet need 
to discover new therapies or effective combination immunotherapy to enhance, improve, or 
restore the responses to anti-PD-1 therapy. 
This study (ION-01-ALKS4230) will enroll patients who have received prior anti-PD-1 antibody 
therapy (pembrolizumab or nivolumab) as their last treatment or those receiving ongoing current 
anti-PD-1 antibody therapy who have not achieved a CR. Programmed cell death 
protein-1:programmed cell death ligand-1 (PD-L1) (henceforth referred to as PD-[L]1) inhibitors 
are effective in small subsets of virtually every histologic type of cancer, yet most treated 
patients fail to benefit. Moreover, many of the tumors that respond eventually relapse. Therefore, 
it is highly likely that, in the near future, patients with stable disease (SD) or progressing on anti-
PD-(L)1 therapy will likely be the largest single category of patients in the US. In the long-term 
follow-up analysis of the KEYNOTE-012 study of single agent pembrolizumab conducted in 
192 patients with HNSCC, the objective response rate was 18% (95% CI, 13% to 24%) (Mehra 
et al, 2018). Among the subset of patients achieving a response, the median time to best response 
 
 
 
 
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was 2 months (range, 2 to 17 months). 
 
 
 
 
 
Discerning the character of the tumors in patients who are not achieving complete regression on 
PD-(L)1 inhibition with anti-PD1 or anti-PD-L is essential. Thus, pretreatment biopsies will be 
mandated. At present, the tumors most likely to respond to anti-PD-1 are those with an increased 
number of mutations and thus abnormal proteins containing potentially immunogenic epitopes 
and infiltration of T cells capable of recognizing the abnormal proteins. Mechanisms by which 
tumors fail to respond to anti-PD-1 are not yet comprehensively defined
 
 
 There are likely to be many more redundant and 
non-redundant mechanisms of failure. Presumably, some mechanisms of failure will be rescued 
by ALKS 4230 (
 
 
) and some will not.  
While it is not currently possible to hypothesize the frequency or proportion of each mechanism, 
we believe that biopsies from participants prior to and during therapy will provide insight into 
purported mechanisms of failure or success to generate hypotheses that will provide the 
foundation for future study design.  
Assessment of whether addition of ALKS 4230 can induce remission for patients with tumors 
that do not respond to anti-PD-1 treatment is the essential goal of the study. Understanding 
whether ALKS 4230 alters the number of NK cells and T cells within tumors is also critical. 
Thus, the post-treatment (second) biopsy will be collected during Week 2 (Cycle [C] 1, 
Day [D] 12 or at any time from C1D8 through C1D19). 
The study population designates patients with advanced or recurrent HNSCC who are either 
refractory and progressive on prior anti-PD-(L)1 therapy or have failed to obtain response or 
tumor regression to anti-PD-1 therapy for more than 8 weeks to receive ALKS 4230 in 
combination with pembrolizumab. Patients in this population are as follows:  
Group 1 (Cohorts 1 and 2) will consist of all patients with current SD (for at least 12 weeks) or 
partial response (PR) with no further reduction in tumor size or response for ≥8 weeks (ie, PR 
and not further improving).  
Group 2 (Cohorts 3 and 4) will consist of patients with progressive disease (PD) with no prior 
response to anti-PD-(L)1 therapy after ≥8 weeks on anti-PD-(L)1 or current PD after prior 
achievement of a best response of SD or PR and after ≥8 weeks on anti-PD-(L)1 therapy. 
HNSCC was chosen due to the high unmet need in this difficult-to-treat patient population with 
no effective therapeutic options for a number of reasons: 1) the demonstrated efficacy and recent 
approval of pembrolizumab for previously platinum-experienced recurrent or metastatic 
HNSCC, 2) the ease of serial biopsies in easily accessible sites of tumor in a proportion of 
patients, and 3) the responses to the combination of ALKS 4230 and pembrolizumab being 
 
 
 
 
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readily and easily assessable. However, if efficacy or response is observed, the combination 
could be tested in many different cancers. 
This study will be performed in collaboration with the Immune Oncology Network (ION), who 
will perform activities related to, but not limited to, oversight and management of clinical sites, 
medical monitoring, and laboratory analysis services. 
5.3. 
Dose Selection 
5.3.1. 
Pembrolizumab 
The pembrolizumab dose of 200 mg Q3W is the approved dose for the treatment of patients with 
HNSCC (Keytruda USPI). 
5.3.2. 
ALKS 4230 
All patients in this study will be given ALKS 4230 at a daily dose of 3 µg/kg for 5 consecutive 
days on Days 1 through 5 of the first week of each 3-week treatment cycle.  
A first-in-human (FIH) clinical study with ALKS 4230 has been initiated and is currently 
ongoing (ALK4230-A101). This study is being conducted in patients with advanced solid tumors 
who are refractory or intolerant to therapies known to provide clinical benefit. Patients are 
administered ALKS 4230 by a 30-minute intravenous (IV) infusion daily for 5 days followed by 
an off-treatment period (as described in the ALK4230-A101 protocol) in repeating cycles. 
Dosing is repeated every 21 days, except during the first treatment cycle, which is 14 days. 
 
 
 
LT 
definitions were subsequently amended to loosen DLT criteria and allow continued dose 
escalation. 
 
 
 
 
 
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6. 
STUDY OBJECTIVES  
6.1. 
Primary Objective 
The primary objective of this study is to estimate the response rate to ALKS 4230 in combination 
with pembrolizumab in patients with HNSCC who have previously received anti-PD-(L)1 
therapy but who have not achieved a CR. The primary objective will be assessed for the 
following 2 groups:  
• Group 1: Patients with SD, defined as ≥12 weeks of SD per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 criteria, or patients with PR with no further 
reduction in tumor size or response (ie, PR and not improving further) for ≥8 weeks 
on prior anti-PD-(L)1 therapy 
• Group 2: Patients with PD with no prior response to anti-PD-(L)1 therapy after 
≥8 weeks on anti-PD-1 therapy or patients currently with PD after prior achievement 
of a best response of SD or PR and after ≥8 weeks on anti-PD-(L)1 therapy. 
6.2. 
Secondary Objectives 
• To evaluate the DOR, progression-free survival (PFS), time to progression (TTP), and 
OS of patients with advanced or recurrent HNSCC receiving pembrolizumab plus 
ALKS 4230 
• To evaluate the safety and tolerability of pembrolizumab plus ALKS 4230 
6.3. 
Exploratory Objectives 
• To evaluate whether assessment of pretreatment biopsies from patients who have 
failed to achieve a CR on therapy with anti-PD-(L)1 can identify a subset of patients 
who are likely to respond to the addition of ALKS 4230
 
• To evaluate whether a second biopsy, 
, can identify 
changes in tumors that will predict response or failure to the addition of ALKS 4230 
 
 
• 
 
 
 
 
 
 
 
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7. 
SELECTION AND WITHDRAWAL OF PATIENTS  
Each patient must meet all of the inclusion and none of the exclusion criteria to be qualified to 
participate in this study.  
7.1. 
Patient Inclusion Criteria 
1. Is ≥18 years of age. 
2. Is willing and able to provide informed consent. 
3. Is willing and able to follow the study procedures as outlined in the protocol. 
4. Must have a histologically or cytopathologically confirmed diagnosis of HNSCC region 
that is locally advanced or recurrent and no longer amenable to local surgical or radiation 
therapy and/or with evidence of metastatic disease. Both HPV-positive and -negative 
patients will be included. 
5. Must have had prior PD-1:PD-L1 inhibition therapy with anti-PD-(L)1 therapy as the 
most recent systemic therapy with 
a. (Group 1, Cohort 1) current SD (for ≥12 weeks by RECIST criteria v1.1) or  
b. (Group 1, Cohort 2) current PR with no further reduction in tumor size or response 
for ≥8 weeks (ie, PR and not further improving) 
c. (Group 2, Cohort 3) current PD with no prior response to anti-PD-(L)1 therapy after 
≥8 weeks on anti-PD-(L)1 or  
d. (Group 2, Cohort 4) current PD after prior achievement of a best response of SD or 
PR and after ≥8 weeks on anti-PD-(L)1 therapy 
Some minimal intervening localized palliative radiotherapy or ablation therapy may 
be allowed upon review and agreement by the ION and Alkermes Medical Monitors. 
6. Must have disease that is measurable by RECIST v1.1 criteria as determined by the 
treating physician and not confounded by prior treatment such as radiation. Patients with 
only 1 site of disease must be able to provide adequate tissue samples at the time of 
biopsy that will not affect the tumor size per RECIST v1.1 criteria.  
7. Patients who have received standard or investigational anti-PD-(L)1 agents as the most 
recent systemic therapy must wait at least 3 weeks (with the exception of an anti-PD-[L]1 
inhibitor that is dosed Q2W and in consultation with the ION and Alkermes Medical 
Monitors, in which case patients must wait at least 2 weeks) before enrollment into the 
study or 4 weeks if the half-life of the investigational agent is not known. Patients who 
have received standard or investigational agents other than anti-PD-(L)1 agents 
(including agents as part of a combination regimen with an anti-PD-[L]1 agent) must wait 
8 weeks before enrollment into the study, unless discussed with and approved by the ION 
and Alkermes Medical Monitors on an individual basis. 
8. Patients must be willing to provide tumor tissue adequate for biomarker correlative 
studies at the time points specified in the protocol.  
 
 
 
 
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9. Patients should have readily accessible tumor for biopsy pre- and post-pembrolizumab 
and ALKS 4230 combination regimen. Biopsy should be excisional, incisional, or core 
needle and large enough to show tissue architecture.  
10. Have a performance status of ≤2 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale. 
11. Demonstrate adequate organ function as defined in Table 3. All screening laboratories 
should be performed within 10 days of treatment initiation. 
Table 3: 
Laboratory Values Defining Adequate Organ Function 
System 
Laboratory Value 
Hematological 
ANC 
≥1,000/μL without hematopoietic growth factor support 
Platelet count 
≥100,000/μL without transfusion support 
Hemoglobin 
≥9 g/dL  
Renal 
Serum creatinine OR 
Measured or calculateda CrCl 
(glomerular filtration rate [GFR] can also 
be used in place of creatinine or CrCl) 
≤1.5×ULN OR 
 
≥60 mL/min  
Hepatic 
Serum total bilirubin 
≤1.5×ULN OR 
Direct bilirubin ≤ULN for patients with total bilirubin levels 
>1.5×ULN 
AST and ALT  
≤2.5×ULN OR 
≤5×ULN for patients with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
INR or PT 
 
aPTT 
≤1.5×ULN unless patient is receiving anticoagulant therapy. 
If the patient is receiving anticoagulant therapy, the INR or PT 
needs to be within the therapeutic range of intended use of 
anticoagulants or deemed a safe level for the proposed biopsies 
by the biopsy surgeon or interventional radiologist.  
 
≤1.5×ULN unless patient is receiving anticoagulant therapy. 
If the patient is receiving anticoagulant therapy, the aPTT 
needs to be within the therapeutic range of intended use of 
anticoagulants or deemed a safe level for the proposed biopsies 
by the biopsy surgeon or interventional radiologist. 
Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; CrCl=creatinine clearance; INR=international normalized 
ratio; PT=prothrombin time; ULN=upper limit of normal 
a CrCl should be calculated per institutional standard. 
 


 
 
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12. Female patients of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
13. Is willing to abide by the contraception requirements for the duration of the study 
(additional details regarding contraception requirements are provided in Section 8.4.1). 
7.2. 
Patient Exclusion Criteria 
1. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (inhaled or 
topical steroids are allowable) or any other form of immunosuppressive therapy within 
7 days prior to the first dose of study drug. 
2. Has active tuberculosis (TB; Bacillus tuberculosis). 
3. Has hypersensitivity to pembrolizumab, ALKS 4230, or any of their excipients. 
4. Has prior Grade ≥3 immune-related toxicities requiring systemic immunosuppressant 
treatment that were attributable or possibly attributable to PD-1 immune checkpoint 
blockade. Has toxicities deemed reversible from prior therapy, including anti-PD-1, that 
have not recovered to baseline or Grade ≤1. Patients with persistent Grade ≤2 neuropathy 
are an exception to this criterion and may qualify for the study. 
a. Note: If patient received major surgery, the patient must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy.  
5. Has had a prior dose of anti-PD-(L)1 therapy within 3 weeks of Study Day 1, with the 
exception of an anti-PD-(L)1 inhibitor that is dosed Q2W and in consultation with the 
ION and Alkermes Medical Monitors. 
6. Has a known history of additional malignancy within 2 years or current additional 
malignancy that is progressing or requires active treatment. Exceptions include basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy, in situ cervical cancer, or treated prostate cancer with a 
prostate-specific antigen value of <0.01 ng/mL. 
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with previously treated brain metastases may participate, provided 
that they are stable (without evidence of progression by imaging for at least 4 weeks prior 
to the first dose of study drug and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using steroids for at 
least 7 days prior to study drug. This exception does not include carcinomatous 
meningitis, which is excluded regardless of clinical stability.  
8. Has known history of, or any evidence of, non-infectious interstitial pneumonitis that 
required steroids or current pneumonitis, or oxygen requirement for any reason in the past 
28 days. 
9. Has an active major infection requiring systemic therapy within 1 week of starting study 
drug. 
 
 
 
 
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10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the patient’s participation for 
the full duration of the study, or is not in the best interest of the patient to participate, in 
the opinion of the treating Investigator.  
11. Has known psychiatric or substance abuse disorders or a social situation that would 
interfere with cooperation with the requirements of the study. 
12. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
the last dose of study drug (see Section 8.4.1 for additional details). 
13. Known active infection with hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or 
hepatitis C (hepatitis C virus [HCV] RNA [qualitative]) detected.  
14. Has any finding that, in the view of the Investigator, would compromise the safety of the 
patient or affect their ability to adhere to the protocol visit schedule or fulfill visit 
requirements. 
15. Is Investigator-site personnel, an immediate family of the Investigator-site personnel, 
employed by Alkermes or ION, or an immediate family member of an Alkermes or ION 
employee. 
16. If, in the opinion of the Investigator (and/or Sponsor), the patient is unsuitable for 
enrollment in the study.  
17. Has significant known cardiovascular impairment (New York Heart Association 
Congestive Heart Failure >Grade 2, unstable angina, myocardial infarction within the 
previous 6 months prior to the first dose of investigational drug, or existing serious 
cardiac arrhythmia). 
18. Has chronic or acute gastrointestinal (GI) disorders resulting in diarrhea of any severity 
grade; patient is using chronic anti-diarrheal supportive care (more than 3 days/week) to 
control diarrhea in the 28 days prior to the first dose of investigational drug. 
19. Has known cirrhosis diagnosed with Child-Pugh Class A or higher liver disease. 
7.3. 
Patient Withdrawal and Discontinuation 
A patient may be discontinued from the study at any time if the patient or Investigator 
determines that it is not in the best interest of the patient to continue participation. Reasons for 
discontinuation include:  
• Adverse event (see Section 12.1.) 
• Disease progression 
− For unconfirmed radiographic disease, see Section 8.3.10. 
− A patient may be granted an exception to continue on treatment with confirmed 
radiographic progression if the patient is clinically stable and upon written 
agreement from both ION and Alkermes Medical Monitors (see Section 8.3.10). 
• Intercurrent illness that prevents further administration of treatment 
 
 
 
 
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• The need for administration of an excluded or prohibited medication 
• Loss to follow-up 
• Withdrawal of consent 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Other 
If a patient withdraws from the study for any reason, any ongoing adverse events (AEs) will be 
followed until resolution, until deemed stable by the Investigator, until initiation of new 
anticancer therapy, or until the patient is deemed by the Investigator to be lost to follow-up. If, in 
the opinion of the Investigator, it is necessary to monitor a patient beyond the Safety Follow-up 
Visit, the follow-up period may be extended as necessary. In such instances, the Sponsor and the 
Investigator will agree to an acceptable follow-up schedule.  
In the event that a patient chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the patient’s 
rights. Enrolled patients are to be asked to return to the clinic for an End of Treatment (EOT) 
Visit. The EOT Visit should be scheduled as close as possible to the patient’s last dose, and early 
termination assessments will follow the assessments scheduled to be conducted at the EOT Visit. 
If the patient fails or refuses to return to the study center, an attempt must be made to contact the 
patient by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the patient’s study record. 
The Investigator must maintain a record of all patients who fail to complete the study. The 
reason for study discontinuation will be documented and made on the appropriate electronic case 
report form (eCRF). If a patient is lost to follow-up, a reasonable attempt to contact the patient 
must be made and documented. 
The Sponsor reserves the right to terminate the study at any time for any reason. 
7.3.1. 
Discontinuation of Study Drug After Complete Remission 
 
 
7.4. 
Replacement of Patients 
Patients who do not receive all doses of ALKS 4230 and pembrolizumab in Cycle 1 will be 
replaced, unless they missed a dose due to toxicity, as assessed by the Investigator. Patients who 
miss a dose of ALKS 4230 and pembrolizumab in Cycle 1 due to toxicity will not be replaced.  
 
 
 
 
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Patients who do not provide a second biopsy may be replaced at the discretion of the 
Investigator. 
 
 
 
 
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CONFIDENTIAL 
8. 
STUDY DESIGN 
8.1. 
Overall Study Design and Plan 
The study will assess the antitumor efficacy of ALKS 4230 in combination with pembrolizumab 
in patients with advanced, recurrent, and/or HNSCC on treatment with an anti-PD-(L)1 antibody 
(pembrolizumab or nivolumab) without having achieved a CR.  
The study is a multi-center, Phase 2, open-label therapy study in collaboration with ION. Patients 
must have received anti-PD-(L)1 therapy prior to enrollment into the study. After enrollment in 
the study, ALKS 4230 with pembrolizumab will be administered to 4 cohorts of patients with 
advanced, recurrent, and/or metastatic HNSCC who have received anti-PD-(L)1 therapy whose 
current response is as follows:  
• Cohort 1: SD, defined as ≥12 weeks of SD per RECIST criteria;  
• Cohort 2: PR with no further reduction in tumor size or response for ≥8 weeks (ie, PR 
and not improving further)  
• Cohort 3: PD with no prior response to anti-PD-(L)1 therapy after ≥8 weeks on anti-
PD-(L)1, or  
• Cohort 4: Current PD after prior achievement of best response of SD or PR and after 
≥8 weeks on anti-PD-(L)1 therapy 
Patients will be administered the combination of ALKS 4230 and pembrolizumab. For 
simplification, the 4 cohorts of patients will be combined into 2 arms:  
• Group 1 will consist of all patients with current SD or PR (Cohorts 1 and 2) who are 
not progressing or further demonstrating reductions in tumor size.  
• Group 2 will consist of patients with PD (Cohorts 3 and 4). 
Baseline tumor biopsy will be required at the time of study entry after screening procedures have 
been completed and prior to first administration of combination regimen to assess each patient’s 
tumor characteristics in an effort to identify patients with tumors that may have limited 
pembrolizumab efficacy or potential response to anti-PD-1/ALKS 4230 combination. Tumors 
will be assessed for quantity and character of tumor-infiltrating T cells and other leukocytes, and 
for quantitative assessment of PD-L1 expression, gene signatures that correlate with response or 
lack of response
 
 
Patients will also have a post-treatment (second) biopsy at C1D12, or at any time from C1D8 
through C1D19, to assess whether the addition of ALKS 4230 to the treatment regimen alters the 
TME and what changes on therapy (immunopharmacodynamics) predispose to responses to the 
combination.  
The study plans to enroll 
 evaluable patients for Groups 1 and 2, 
 The 
number of patients enrolled into each cohort within each group will be determined at the time of 
enrollment, based on the patient’s response to previous treatment It will be at the discretion of 
 
 
 
 
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Alkermes and ION to expand a particular cohort of interest 
 
.  
Pembrolizumab will be administered according to the standard regimen of 200 mg flat dose IV 
Q3W. ALKS 4230 will be administered IV at a daily dose of 3 µg/kg, given daily on 
5 consecutive days on Days 1 through 5 of the first week of each 3-week treatment cycle.  
ALKS 4230 may be continued until toxicity develops. If a toxicity attributed to ALKS 4230 
occurs, dosing for both pembrolizumab and ALKS 4230 will be held. After recovery from an AE 
that meets dose hold criteria, the patient may resume at full dose of pembrolizumab and full or 
reduced dose of ALKS 4230 in subsequent cycles with consultation from the Medical Monitor or 
may discontinue from the study.
 
 
 
Patients with tumors who respond to treatment will continue until the following: 
• Confirmed progression occurs (upon agreement with the ION and Alkermes Medical 
Monitors, patients tolerating therapy and receiving clinical benefit may be allowed to 
stay on study for up to 1 year) 
• Until unacceptable toxicity occurs 
• Other criteria for discontinuation occur 
Safety and tolerability will be assessed and reported using standard Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 criteria. Safety will be monitored by the study 
Principal Investigator (PI), participating site PIs, the ION Coordinating Center PI and staff, and 
representatives from Alkermes. Details pertaining to the Safety Review Committee (SRC), 
including participants, frequency of meetings, and criteria that would trigger ad hoc meetings, 
are described in the SRC Charter. 
If the unacceptable AEs (defined in Section 12.2) observed are typical of known pembrolizumab 
and/or ALKS 4230 toxicities, the following will be considered: (1) revising the protocol 
eligibility requirements to decrease the likelihood of toxicities, (2) modifying the dose or 
schedule, or (3) allowing the study to proceed as designed assuming that patients in this study 
will have fatal diseases and few other treatment options. The risk/benefit ratio will need to be 
evaluated in this situation. 
If unexpected, unacceptable AEs are considered to be related to concurrent administration of 
ALKS 4230 and pembrolizumab, the PI, participating site PIs, the ION Coordinating Center PI 
and staff, and representatives from Alkermes will consider revising the protocol eligibility 
requirements to decrease the likelihood of toxicities or may consider allowing the study to 
proceed as designed given the risk/benefit ratio for this population. 
Study design schematics are provided in Figure 1 and Figure 2. 
 
 
 
 
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CONFIDENTIAL 
Figure 1: 
Study Design Schematic 1 
 
Pembrolizumab regimen: 200 mg once Q3W by IV infusion 
ALKS 4230 regimen: 3 µg/kg, given daily on 5 consecutive days on Days 1 through 5 of the first week of each 
3-week treatment cycle. 
Abbreviations: CR=complete remission; HNSCC=squamous cell carcinoma of the head and neck; PD=progressive 
disease; PD-(L)1=programmed cell death ligand-1; PR=partial response; SD=stable disease; Q3W=every 3 weeks 
Figure 2: 
Study Design Schematic 2 
 
Abbreviations: IV=intravenous; Q3W=every 3 weeks. 
8.2. 
Schedule of Assessments 
The schedule of assessments for treatment and post-treatment follow-up is shown in Table 4. The 
schedule of assessments for long-term follow-up is shown in Table 5. 
Premature discontinuation procedures are provided in Section 7.3. 
 
 
 
 
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Table 4: 
Schedule of Assessments and Study Visits 
Treatment 
Cyclea 
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycle 
(Repeat for 
up to 1 year) 
End 
of 
Txa 
Post-treatment Follow-up 
Weeks 
Scree
ning 
w
1 
w
2 
w
3 
w
4 
w
5 
w
6 
w
7 
w
8 
w
9 
w
10 
w
11 
w  
12 
w
13 
w
14 
w
15 
w
16 
w 
17 
w
18 
Safety 
FU 
Disease 
Assess-
mentb 
Survi
-val 
FUc 
Scheduling 
window 
(days)d 
-28 to 
-1 
days 
 
 
 
-1/ 
+3 
 
 
-1/ 
+3 
 
 
-1/ 
+3 
 
 
-1/ 
+3 
 
 
-1/ 
+3 
 
 
At 
time 
of 
D/C 
30 
days 
±5 post 
D/C 
Every 8 
weeks 
post 
D/C for 
up to 2 
years 
Every 
12 
week
s for 
up to 
2 
years 
Pembrolizu-
mab 
 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
 
 
 
ALKS 4230 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
 
 
 
 
Antipyretics 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Administrative Procedures 
Informed 
Consent 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medicationsf 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
Alkermes, Inc. 
Protocol ION-01-ALKS4230 
 
 
 
 
 
 
CONFIDENTIAL 
Table 4: 
Schedule of Assessments and Study Visits (Continued) 
Treatment 
Cyclea 
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycle 
(Repeat for 
up to 1 year) 
End 
of 
Txa 
Post-treatment Follow-up 
Weeks 
Scree
ning 
w
1 
w
2 
w
3 
w
4 
w
5 
w
6 
w
7 
w
8 
w
9 
w
10 
w
11 
w  
12 
w
13 
w
14 
w
15 
w
16 
w 
17 
w
18 
Safety 
FU 
Disease 
Assess-
mentb 
Survi
-val 
FUc 
Clinical Procedures/Assessments 
Review AEsg 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Xh 
Xh 
 
Full Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Directed 
Physical 
Examination 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Vital Signs, 
Weight, and 
Heighti 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
ECOG 
Performance 
Statusj 
Xj 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
12-lead ECGk 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Laboratory Assessments (Safety Labs) 
HBsAg, anti-
HCV, and HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
– Urine or 
Serum β-hCGl 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
PT/INR and 
aPTTm 
Xj 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Table 4: 
Schedule of Assessments and Study Visits (Continued) 
Treatment 
Cyclea 
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycle 
(Repeat for 
up to 1 year) 
End 
of 
Txa 
Post-treatment Follow-up 
Weeks 
Scree
ning 
w
1 
w
2 
w
3 
w
4 
w
5 
w
6 
w
7 
w
8 
w
9 
w
10 
w
11 
w  
12 
w
13 
w
14 
w
15 
w
16 
w 
17 
w
18 
Safety 
FU 
Disease 
Assess-
mentb 
Survi
-val 
FUc 
Laboratory Assessments (Safety Labs) (Continued) 
CBC with 
Differentialn 
Xj 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Xo 
 
 
Complete 
Serum 
Chemistry 
Paneln 
Xj 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Xo 
 
 
Urinalysisn 
Xj 
X 
 
 
X 
 
 
X 
 
 
Xp 
 
 
 
 
 
X 
 
 
 
Xo 
 
 
TSH, Cortisol, 
and ACTHq 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
Xr 
 
 
 
 
 
X
s 
 
 
 
Xs 
 
 
 
 
 
Xs 
 
 
Xb,t 
 
Xb 
 
Tumor Biopsies/Archival Tissue and Microbiota Collection 
Archival or 
Newly Obtained 
Tumor Biopsy 
(for Tumor 
T-cell 
Clonality; GEP 
studies, and 
Sequencing and 
TMB analysis) 
 
X
u 
X
v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Table 4: 
Schedule of Assessments and Study Visits (Continued) 
Treatment 
Cyclea 
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycle 
(Repeat for 
up to 1 year) 
End 
of 
Txa 
Post-treatment Follow-up 
Weeks 
Scree
ning 
w
1 
w
2 
w
3 
w
4 
w
5 
w
6 
w
7 
w
8 
w
9 
w
10 
w
11 
w  
12 
w
13 
w
14 
w
15 
w
16 
w 
17 
w
18 
Safety 
FU 
Disease 
Assess-
mentb 
Survi
-val 
FUc 
Tumor Biopsies/Archival Tissue and Microbiota Collection (Continued) 
Stool Samplew 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Drawsx 
Immuno-
genicity of 
ALKS 4230 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X (14 
days 
post 
D/C) 
 
 
 
 
Immuno-
phenotyping of 
PBMC 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
T- and NK-cell 
Function 
Analysis 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Plasma 
Cytokine 
Assays 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kyn/Trp Ratio, 
Arginine 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Abbreviations: A=ALKS 4230: 3 µg/kg, daily for 5 consecutive days on Days 1 through 5 of the first week of each 3-week treatment cycle. 
ACTH=adrenocorticotropic hormone; AE=adverse event; aPTT=activated partial thromboplastin time; C=Cycle; CBC=complete blood count; CIML=Central 
Immune Monitoring Laboratory; CTCAE=Common Terminology Criteria for Adverse Events; D=Day; D/C=discontinuation; ECG=electrocardiogram; 
ECI=events of clinical interest; ECOG=Eastern Cooperative Oncology Group; FNA=fine needle aspiration; FU=follow-up; GEP=gene expression profiling; 
HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HPV=human 
papillomavirus; ID=identification; INR=international normalized ratio; Kyn=kynurenine; NCI=National Cancer Institute; NK=natural killer; 
P=Pembrolizumab: 200 mg flat dose, once Q3W, starting Cycle 1, Day 1 for up to 1 year; PD=progressive disease; PD-L1=programmed death ligand-1; 
 
 
 
 
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CONFIDENTIAL 
PBMC=peripheral blood mononuclear cell; PT=prothrombin time; Q3W=every 3 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; 
SAE=serious adverse event; TMB=tumor mutational burden; Trp=tryptophan; TSH=thyroid-stimulating hormone; Tx=treatment; w=Week (visit). 
a In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified. Treatment 
cycles are 3 weeks; however, the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in 
Section 9.1.1 and Section 9.1.2. 
b In patients who discontinue study therapy, every effort should be made to continue monitoring their disease status by radiologic imaging per local standard of 
care or Investigator clinical judgment every 8 weeks for up to 2 years until (1) the initiation of new therapy, (2) death, or (3) the end of the study, whichever 
occurs first. 
c After the start of new anticancer treatment or documented disease progression by local imaging review, the patient should be contacted by telephone every 
12 weeks (±1 week) to assess for survival status for up to 2 years. 
d In general, the window for each visit is -1/+3 days unless otherwise noted. Pembrolizumab is given on Day 1 of each cycle with a -1/+3-day window. ALKS 
4230 is given daily on 5 consecutive days on Days 1 through 5 of the first week of each 3-week treatment cycle. Day 1 of each 5-day dosing period will have a 
-1/+3-day scheduling window; however, all subsequent days within a cycle (Days 2 to 5) must be administered on their scheduled day. Refer to Section 9.5.2 
for management of skipped dosing days. 
e Written consent must be obtained prior to performing any protocol-specified procedure. Consent should include option to copy relevant imaging for central 
review by the manufacturer, enabling confirmation of Investigator-determined responses. Results of a test performed prior to the patient signing consent as part 
of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (eg, within 28 days prior to the first dose 
of study drug). A patient ID number will be assigned when the patient is enrolled. 
f Prior medications – Record all medications taken within 30 days of Screening Visit. Concomitant medications – Enter new medications started within 28 days 
before the first dose of study drug through the Safety Follow-up Visit. Record all medications taken for AEs. 
g AEs and laboratory safety measurements will be graded per NCI CTCAE v5.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness. The Week 3 AE review can be captured via telephone; no visit is required. 
h Record all AEs occurring within 30 days after the last dose of study drug. Report all SAEs (related and unrelated to study drug) and ECIs occurring up until 
90 days after the last dose of study drug or 30 days after the start of new anticancer treatment, whichever comes first. Afterwards, report only SAEs and ECIs 
that are related to study drug. 
i Vital signs include temperature, pulse, respiratory rate, weight, and blood pressure. Height will be measured at Visit 1 only. 
j ECOG Performance Status and laboratory tests for screening are to be performed within 10 days prior to the first dose of study drug. 
k ECGs should be performed on Day 1, Day 3, and Day 5 of each cycle. ECGs should be performed in triplicate approximately 5 minutes apart at each time point 
assessed. ECGs will be obtained predose of pembrolizumab on Cycle 2 Day 1. ECGs should also be obtained predose of ALKS 4230, at the end of infusion, 
and 1 hour (±15 minutes) after the completion of administration of ALKS 4230. 
l 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 Dose 1 of each cycle is administered for all cycles.  
m Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures and before collection of the post-treatment (second) biopsy for all 
patients. Any patient receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study. 
n After Cycle 1, laboratory samples can be collected up to 72 hours prior to Day 1 (CBC with differential; complete serum chemistry panel, including 
magnesium, calcium, and phosphorus; and urinalysis). CBC and complete serum chemistry panel should also be done up to 72 hours prior to Day 1 of the 
ALKS 4230 infusion. 
o Unresolved abnormal laboratories that are drug-related AEs should be followed until resolution. Laboratories do not need to be repeated after the end of 
treatment if laboratories are within normal range. 
 
 
 
 
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CONFIDENTIAL 
p To be repeated every 2 cycles after Cycle 4. 
q TSH, cortisol, and ACTH should be measured at baseline and every other cycle (every 6 weeks). Cortisol should be measured in the morning. 
r The initial tumor imaging will be performed within 28 days prior to the first dose of study drug. Scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of study drug. Local reading 
(Investigator assessment with site RECIST radiology reading) will be used to determine eligibility and for patient management. 
s The first on-study imaging time point will be performed at 6 weeks (±7 days) after the first dose of study drug, then within 7 days prior to every second cycle, 
or more frequently if clinically indicated. The same imaging technique should be used in a patient throughout the study. Local reading (Investigator assessment 
with site RECIST radiology reading) will be used to determine eligibility and for patient management. 
t In patients who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment 
discontinuation (ie, date of discontinue ± 4-week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at 
treatment discontinuation is not mandatory. 
u Baseline tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy (FNA not adequate) from patients with oropharynx cancer 
must be tested locally for HPV status (if HPV status not known) prior to enrollment. Baseline tumor tissue from a newly obtained sample must also be provided 
to the CIML for PD-L1 biomarker testing (see Laboratory Manual for additional details). Newly obtained tissue may be obtained up to 42 days prior to 
treatment initiation, as long as the patient has provided study consent. Detailed instructions for tissue collection, processing, and shipment are provided in the 
Laboratory Manual. If the patient gives permission for the future use of additional biospecimen materials, then any leftover tissue that would ordinarily be 
discarded will be stored for future, as-yet-identified testing. 
v The post-treatment (second) biopsy will be performed on the same or similar tumor site during the first cycle of therapy at C1D12, or at any time from C1D8 
through C1D19. 
w Fecal swab/storage devices and instructions must be given to the patient; sample collection to be performed at home by patient and returned to clinical research 
site at the next study visit. 
x Additional information regarding correlative studies is located in Table 16, and additional instructions are provided in the Laboratory Manual. 
 
 
 
 
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CONFIDENTIAL 
Table 5: 
Long-term Follow-up Schedule 
Patient Group 
Imaging 
Follow-up 
AE Tracking 
Patients with SD/PR who continue 
on Tx, no progression, for up to 
1 year  
9 weeks post-treatment start (within 
7 days prior to Cycle 4), then within 
7 days prior to every 3rd cycle 
Follow-up: every 12 weeks ±1 week 
Safety Follow-up Visit at 30 days 
after discontinuation 
Clinic visit every 8 weeks 
Until 90 days after discontinuation or 
30 days after discontinuation if 
patient begins new anticancer therapy 
Patients who progress on-study 
before 1 year 
Per local standard of care 
Safety Follow-up Visit at 30 days 
after discontinuation or before start 
of new therapy, if applicable (in-
clinic) 
Safety Follow-up Visit at 90 days 
after discontinuation (in-clinic 
preferable, by phone possible) 
Survival telephone call every 12 
weeks for up to 2 years 
Until 90 days after discontinuation or 
30 days after discontinuation if 
patient begins new anticancer therapy 
Patients who discontinue treatment 
due to any reason other than 
progression 
Per local standard of care or 
Investigator clinical judgment 
Safety Follow-up Visit at 30 days 
after discontinuation or before start 
of new therapy, if applicable 
Clinic follow-up until toxicity 
resolves or until death 
Until 90 days after discontinuation or 
30 days after discontinuation if 
patient begins new anticancer therapy 
Patients who achieve CR on Tx 
(after at least 24 weeks of Tx + 
2 doses post-CR imaging) 
After discontinuation of treatment: 
Follow-up: every 12 weeks ±1 week 
OR at clinical signs/symptoms of 
progression 
Safety Follow-up Visit at 30 days 
after discontinuation 
Clinic visit every 8 weeks 
Until 90 days after discontinuation or 
30 days after discontinuation if 
patient begins new anticancer therapy 
Abbreviations: AE=adverse event; CR=complete remission; NA=not applicable; PR=partial response; SD=stable disease; Tx=treatment.  
 
 
 
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CONFIDENTIAL 
8.3. 
Study Procedures Descriptions 
Details of the study procedures are described below. The overall schedule of assessments is 
provided in Table 4. 
8.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the patient by the 
Investigator or designated study personnel as outlined in Section 16.3. 
Prior to the administration of any study-specific procedures, authorized study personnel will 
obtain written informed consent from each potential patient. Consent should include the option to 
copy relevant imaging for central review by the manufacturer to enable confirmation of 
Investigator-determined responses. 
8.3.2. 
Eligibility Review 
An eligibility review will be conducted by the Investigator at the visits specified in Table 4 using 
the patient inclusion criteria in Section 7.1 and exclusion criteria in Section 7.2. 
8.3.3. 
Demographics and Medical History 
Patient’s demographic data and medical history will be reviewed and documented at the time 
point(s) specified in Table 4. Tumor measurements should be collected prior to the patient’s 
enrollment on the study. Measurements to collect should include any measurements RECIST 
made during the patient’s previous treatment with an anti-PD-(L)1 agent. 
8.3.4. 
Prior and Concomitant Medication Review 
At the time point(s) specified in Table 4, prospective patients will be asked about the 
medications they have taken in the last 28 days, including prescription and nonprescription 
medications, vitamins, and supplements.  
The Investigator will record the following data on all medications used by the patient: name, 
dose, regimen, route of administration, start and stop dates, and the indication for use.  
Prohibited medications are described in Section 8.4.2. 
8.3.5. 
Infusion-Type Reactions 
ALKS 4230 may be associated with infusion-type reactions. Infusion reactions should be treated 
at the discretion of the Investigator. The National Cancer Institute CTCAE v5.0 describes 
multiple types of infusion reactions:  
1. Allergic reactions 
2. Anaphylaxis 
3. Cytokine release syndrome  
Patients who experience Grade 3 or 4 infusion reactions should not be rechallenged with 
ALKS 4230. 
 
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Infusion-type reactions associated with the use of pembrolizumab should be managed in 
accordance with the prescribing information for pembrolizumab (Keytruda USPI). 
8.3.6. 
Vital Signs and Weight 
Vital signs (ie, weight, blood pressure, pulse, respiratory rate, and body temperature) will be 
assessed at the time point(s) specified in Table 4. Height will be measured at screening (Visit 1) 
only. Blood pressure, pulse, and respiratory rate will be measured after the patient has been 
resting in a seated or supine position for at least 5 minutes. 
8.3.7. 
Physical Examination 
A physical examination will be performed at the time point(s) specified in Table 4. For cycles 
that do not require a full physical exam per the study flow chart, the Investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to study drug 
administration. 
8.3.8. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be conducted at the time point(s) specified in Table 4.  
8.3.9. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG Performance Status assesses the patients’ activity status and will be assessed at the 
time points specified in Table 4. Possible scores are 0 to 5. Descriptions of activity status are 
presented in Table 6.  
Table 6: 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead 
8.3.10. 
Tumor Imaging and Assessment of Disease 
For the purposes of this study, baseline scans must be done within 28 days before beginning 
treatment. In addition to a baseline scan, the first on-study imaging time point will be performed 
 
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at 6 weeks (± 7 days) after first dose, then within 7 days prior to every second cycle thereafter, or 
more frequently if clinically indicated while the patient is on study.  
Patients whose response converts from PD or SD to PR or from PR to CR will have a 
confirmatory scan for tumor assessments 6 weeks after the response-defining scan. If the patient 
continues on study after confirmatory scan, then the patient would receive scan per regular 
schedule. Thereafter, timing of tumor assessments will depend on whether or not the patient 
continues with study drug (see Table 5 for additional information).  
 
 
 
 
  
 
 
 
 
 
Accumulating evidence indicates that a minority of patients treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. Allowance to continue treatment despite 
initial radiologic progression takes into account the observation that some patients can have a 
transient tumor flare in the first few months after the start of immunotherapy but with subsequent 
disease response. Patients will be permitted to continue on treatment beyond initial RECIST 
v1.1-defined PD as long as they meet the following criteria: 
• Investigator-assessed clinical benefit and no rapid disease progression. 
• Patient continues to meet relevant eligibility criteria, as determined by the ION and 
Alkermes Medical Monitors (or designee) in discussion with the Investigator. 
• Stable performance status. 
• Patient is tolerating study treatment. 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (eg, CNS metastases). 
The decision to continue treatment beyond initial Investigator-assessed progression should be 
discussed with the ION and Alkermes Medical Monitors (or designee) and documented in the 
study records. A follow-up scan should be performed at the next scheduled imaging evaluation 
6 weeks later to determine whether there has been a decrease in the tumor size or continued PD. 
The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
patient is clinically deteriorating and unlikely to receive any benefit from continued treatment. If 
the Investigator feels that the patient continues to achieve clinical benefit by continuing 
treatment, then the patient should remain on the study and continue to receive monitoring 
according to the Schedule of Assessments (Section 8.2), with consultation from the ION and 
Alkermes Medical Monitors.  
 
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Patients may receive study drug while waiting for confirmation of PD if they are clinically stable 
as defined by the following criteria:  
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status  
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
Table 7: 
Tumor Imaging/Assessment for Disease Progression 
Disease 
assessment by 
RECISTv1.1 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at 
approximately 4 to 
6 weeks to confirm 
PD 
May continue 
study drug at the 
Investigator’s 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging at 
approximately 4 to 
6 weeks to confirm 
PD if possible 
Discontinue 
treatment if 
alternative therapy 
is warranted 
Repeat scan 
confirms PD
a 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
NA 
Repeat scan 
shows SD, PR, or 
CR 
Continue regularly 
scheduled imaging 
assessments prior 
to every 3rd cycle
b 
Continue study 
drug at the 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments prior 
to every 3rd cycleb 
May restart study 
drug if condition 
has improved 
and/or clinically 
stable per 
Investigator’s 
discretion 
Abbreviations: CR=complete remission; NA=not applicable; PD=progressive disease; PR=partial response; 
RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease. 
a Patients who are otherwise clinically stable may be continued on study drug, per Investigator discretion. Even if 
the patient remains otherwise stable, study drug will be discontinued if tumor burden increases by 25% or more 
following initial confirmation of progression.  
b Tumor imaging/assessment will be performed at baseline, at 9 weeks, and prior to every 3rd cycle. 
Response and progression for purpose of publication will be evaluated in this study using the 
new international criteria proposed by the revised RECIST v1.1 guideline. Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes will be used in the RECIST criteria. 
 
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Often with immunotherapy, tumors appear larger before they decrease in size. 
 
 
 
. Clinicians are 
encouraged to consider this possibility to avoid stopping potentially effective immunotherapy too 
soon. 
8.3.10.1. Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of consent.  
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (NOTE: Patients who exhibit objective disease 
progression prior to the end of Cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment will be based on the presence, absence, or unequivocal 
progression of the lesions. 
8.3.10.2. Disease Parameters 
Measurable disease: For the purposes of this study, measurable lesions are defined according to 
RECIST v1.1 criteria. All tumor measurements must be recorded in mm (or decimal fractions of 
centimeters). 
NOTE: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by computerized tomography (CT) scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses (not 
followed by CT or magnetic resonance imaging [MRI]), are considered as non-measurable. 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
 
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with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement; in such 
circumstance, the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as a reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or rare cases of unequivocal progression of each should be noted throughout follow-up. 
8.3.10.3. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged and are only assessable by clinical examination. Methods allowable for disease 
evaluation are as follows: 
• Clinical examination: For skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. Clinical lesions 
will only be considered measurable when they are superficial (eg, skin nodules and 
palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (eg, skin 
nodules).  
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable.  
• Conventional CT and MRI: A CT scan may be used to measure the lesion if the CT 
slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (eg, for body scans). For both scanning methods, 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. The modality used at follow-up should be 
the same as was used at baseline, and the lesions should be measured/assessed on the 
same pulse sequence. Ideally, the same type of scanner should be used, and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body 
scans should be performed with breath-hold scanning techniques, if possible. 
• Positron emission tomography (PET)-CT: Combined PET-CT is not always of 
optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical 
 
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diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion 
of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over 
time. 
Fluorodeoxyglucose (FDG)-PET: FDG-PET scanning is optional and may be used to 
complement CT scanning in assessment of progression (particularly possible 'new' disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site 
of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
3. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
NOTE: A ‘positive’ FDG-PET scan lesion means one that is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
Cytology and histology techniques can be used to differentiate between PR and CR in rare cases 
(eg, residual lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or SD is mandatory to 
differentiate between response or SD (an effusion may be a side effect of the treatment) and PD. 
8.3.10.4. Response Criteria 
Evaluation of Target Lesions 
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm. 
PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 
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PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (NOTE: the appearance of one or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
NOTE: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD: Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression should not normally trump target lesion status. It 
must be representative of overall disease status change, not a single lesion increase.  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or PI). 
8.3.10.5. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. Best overall response is described 
in Table 8 for patients with measurable disease and in Table 9 for patients with non-measurable 
disease. 
Table 8: 
Best Overall Response for Patients with Measurable Disease (ie, Target 
Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required 
CR 
CR 
No 
CR 
≥4 weeks confirmationa 
CR 
Non-CR/Non-PD 
No 
PR 
≥4 weeks confirmationa 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
Documented at least once ≥4 weeks 
from baseline 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR, or CR 
Any 
PDb 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
 
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Abbreviations: CR=complete remission; SD=stable disease; PD=progressive disease; PR=partial response; 
RECIST=Response Evaluation Criteria in Solid Tumors. 
a Only for non-randomized studies with response as primary endpoint. 
b In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
See RECIST v1.1 manuscript for further details on what is evidence of a new lesion. 
NOTE: For purposes of this trial, confirmation of response will occur at 6 weeks after the 
response-defining measurements rather than the 4-week point specified in the RECIST v1.1 
criteria. 
Table 9: 
Best Overall Response for Patients with Non-Measurable Disease (ie, 
Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete remission; PD=progressive disease; SD=stable disease 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised 
8.3.10.6. Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or PD is objectively documented (taking as reference for PD the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that PD is objectively documented. 
 
Duration of SD: The duration of SD is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
8.3.11. 
Laboratory Assessments 
Blood and urine samples for laboratory assessments will be collected at the time points specified 
in Table 4. Specific complete blood count (CBC) with differential, complete serum chemistry, 
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 CBC with differential, 
complete serum chemistry, and urinalysis. 
 
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Table 10: 
Clinical Laboratory Assessments 
CBC with Differential 
Complete Serum 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
Total and differential 
white blood cell count 
ANC 
Absolute lymphocyte 
count 
Sodium 
Potassium 
Phosphorus 
Glucose 
Total protein 
BUN 
Serum creatinine 
CrCl 
Albumin 
Total bilirubin 
ALT 
AST 
LDH 
ALK-P 
CO2 or bicarbonatea 
Uric acid 
Calcium 
Chloride 
Magnesium 
Direct bilirubin, if total 
bilirubin is elevated 
above the upper limit of 
normal 
Specific gravity 
Protein 
pH 
Glucose 
Ketones 
Blood 
Microscopic 
examination of 
sediment, only if 
urinalysis dipstick 
results are abnormal 
(2+ or higher) 
Urine pregnancy testb 
Serum β-hCGb 
PT (INR) 
aPTT 
TSH 
Cortisol (morning) 
ACTH 
Abbreviations: ACTH=adrenocorticotropic hormone; ALK-P=alkaline phosphatase; ALT=alanine aminotransferase; 
ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; CBC=complete blood count; CO2=carbon dioxide; CrCl=creatinine clearance; 
hCG=human chorionic gonadotropin; INR=international normalized ratio; LDH=lactic dehydrogenase; 
PT=prothrombin time; TSH=thyroid-stimulating hormone. 
a If considered standard of care in local region. 
b Perform on women of childbearing potential only. If urine pregnancy test results cannot be confirmed as negative, 
a serum pregnancy test will be required. 
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment. After Cycle 1, predose laboratory procedures can be conducted up to 72 hours prior to 
dosing on Day 1 of each cycle. Results must be reviewed by the Investigator or qualified 
designee and found to be acceptable prior to each dose of study drug.  
If a site is unable to collect all specimens due to low hemoglobin or other issues such as vein 
access, specimens should be collected in the following order if required at the visit: 
• Toxicity/safety specimens  
• 
 
 
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• 
 
8.3.11.1. Pregnancy Testing 
A urine/serum pregnancy test will be administered to all women of childbearing potential at the 
time point(s) specified in Table 4. At the Screening Visit, results must be negative for the patient 
to be eligible for the study.  
Section 12.5 provides guidance on the reporting requirements for pregnancies. 
8.3.11.2. Serology Testing 
A blood sample for serology panel testing for hepatitis B surface antigen, anti-hepatitis C 
antibodies, and human immunodeficiency virus will be performed at screening only. 
8.3.12. 
Laboratory Correlative Studies 
Specimens will be collected for several planned correlative studies (summarized in Table 16) at 
the time points specified in Table 4. Many samples will be processed and stored, to be run in 
batches. When blood volume is limited, correlative studies will be considered secondary to tests 
needed to make clinical decisions. Also, testing may be delayed or omitted if collecting the 
specimens may pose a danger to the patient, if samples cannot be processed or assayed, or if 
results are determined to be non-essential to achieving the objectives of the study. 
8.3.12.1. Correlative Studies With Biopsies 
Collection of pretreatment tumor tissue (fresh biopsy via excisional, incisional, or core needle 
and large enough to show tissue architecture) is mandatory; if collecting pretreatment tissue is 
not possible (eg, inaccessible or patient safety concern), submission of archived specimen is 
possible upon agreement from the Sponsor. Obtaining a post-treatment (second) biopsy is 
mandatory in order to achieve protocol objectives and to study the TME post-treatment but may 
be bypassed for patient safety reasons only after discussions with the Sponsor. Biopsy-based 
correlatives are considered exploratory. Prioritization of biopsy specimens will be made based on 
technical considerations that will be included in the Laboratory Manual, total number of samples 
acquired, and feasibility of correlative study based on the above considerations.  
The pretreatment biopsy will be collected after all screening assessments have been performed 
and before the first dose of pembrolizumab and ALKS 4230 on Cycle 1, Week 1, Day 1. The 
pretreatment specimen may be obtained up to 6 weeks (42 days) prior to initiation of treatment 
on Day 1, provided study informed consent has been obtained or the biopsy was performed as 
part of routine patient care. The post-treatment (second) biopsy will be performed on the same or 
similar tumor site during the first cycle of therapy at C1D12 or at any time from C1D8 through 
C1D19. Fine needle aspirates are not allowed for tissue sampling but may be used to localize 
active disease prior to tissue sampling. 
The biopsies will be collected according to clinical site standard operating procedures (SOPs).  
 
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8.3.12.2. Correlative Studies with Blood Draws 
The timing of sample collection for the following assessments is presented in Table 4. 
 
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8.3.12.2.5. Immunogenicity of ALKS 4230 
Patients will be monitored for the presence and development of auto-antibodies to ALKS 4230. 
Serial serum samples will be assessed from baseline, at Day 1 of each cycle, and 14 days after 
the last treatment.  
All patients who met eligibility criteria, had analyzable specimens, and received at least 1 dose 
of ALKS 4230 will be included in the immunogenicity analyses. Subset analysis will 
prospectively be analyzed for all patients completing each complete cycle of ALKS 4230. 
Immune testing will follow a similar scheme with each cycle of ALKS 4230. Serum samples for 
evaluation of anti-ALKS 4230 antibody induction will be obtained from each patient at 
predetermined time points.
 
 
 Remaining serum samples will be stored for potential 
analysis of anti-pembrolizumab antibody induction at a future date.  
NOTE: Blood collection for all immunogenicity samples required must be drawn before the 
patient receives the ALKS 4230 on any scheduled day (see Table 16 for specific laboratory 
tests). 
 
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8.3.13. 
Drug Dispensation and Reconciliation 
Section 9 provides information related to drug dispensing procedures. Study drug will be 
dispensed/administered at the time point(s) specified in Table 4. 
8.3.13.1. Collection of Specimens 
 
 
 
Patients will undergo pretreatment and post-treatment biopsies as part of this protocol. These 
biopsies will serve as specimens for tumor PD-L1 expression and multi-parameter IHC; 
 
 
 
 
 
 
 
 
8.3.13.2. Handling and Shipping of Specimens 
Whole blood samples will be shipped ambient to the CIML for next-day delivery at the same day 
as the blood draw, so that the sample is received at the CIML within 24 hours of blood draw. 
 
 Specific instructions will be detailed in the Laboratory Manual. 
Additionally, 
, whole blood will be processed to PBMC 
 
 at the CIML and stored in liquid nitrogen. 
For 
, plasma and serum samples, 
respectively, will be collected at room temperature and taken to the local laboratory for 
processing. Plasma will be obtained and frozen at -80°C at the local laboratory. Samples will be 
shipped in batches to the CIML and distributed to assay site(s). 
Plasma and serum cryovials will be batch shipped at regular intervals to the CIML on dry ice for 
next-day delivery. The frequency of batch shipments will be determined by the CIML in 
communication with each site.
 
 Specific instructions will be 
detailed in the Laboratory Manual. 
Plasma and serum will be stored at -80°C at the CIML until analysis. The CIML will coordinate 
shipments of plasma and serum to the agreed upon vendor or assay site(s). 
For PD-L1 expression and IHC;
 
 the tissue will be placed in formalin and shipped 
overnight at ambient temperature to the CIML. 
 
 
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 Specific instruction 
will be detailed in the Laboratory Manual.  
The CIML or designate will prepare FFPE blocks and then prepare slides. 
 
 
 
 
8.3.14. 
Randomization 
This is an open-label study. Randomization is not applicable. 
8.3.15. 
Adverse Event Monitoring 
Adverse events will be monitored continuously from the time a patient signs the informed 
consent document until the completion of the Safety Follow-up Visit or final disease assessment 
visit during the post-treatment follow-up (Table 4). Adverse events and serious adverse events 
(SAEs) are defined in Sections 12.1 and 12.2, respectively. Section 9.5.2 provides stopping 
criteria, and Section 12.4 provides guidance on the monitoring and recording requirements for 
AEs. Section 12.5 provides guidance on the reporting requirements for SAEs. 
8.4. 
Study Requirements and Restrictions 
8.4.1. 
Contraception and Pregnancy 
All male and female patients must agree to use an acceptable method of contraception for the 
duration of the study and 120 days after the final dose of study drug unless they are surgically 
sterile or postmenopausal (see below). The following are considered acceptable methods of 
contraception:  
1. Double-barrier protection (eg, a condom with spermicide or a diaphragm with 
spermicide) 
2. Intrauterine device (IUD) 
3. Oral contraceptive pills and other hormonal methods (eg, a vaginal ring, contraceptive 
patch, and contraceptive implant); oral contraceptives should have been initiated at least 
30 days prior to Screening 
Patients who are abstinent are eligible, provided this is the usual lifestyle and preferred 
contraception for the patient, and they agree to use an acceptable contraceptive method should 
they become sexually active. 
Patients who are surgically sterile are exempt from the requirement to use contraception. Women 
who have undergone hysterectomy, bilateral tubal ligation, or bilateral salpingo-oophorectomy 
are considered surgically sterile. Men who have undergone vasectomy are considered surgically 
sterile. Partner vasectomy is not considered an approved acceptable method of contraception for 
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Women who are postmenopausal are also exempt from the requirement to use contraception. For 
the purpose of this study, postmenopausal is defined as the permanent cessation of menstruation 
for at least 12 months prior to screening in women who are 45 years of age or older or 
menopausal levels of follicle-stimulating hormone in the absence of hormone replacement 
therapy for women less than 45 years of age. 
If a patient becomes pregnant while participating in the study, she will be discontinued from 
study drug immediately. The EOT and Safety Follow-up Visits will be scheduled, and the 
pregnancy will be reported to Alkermes. Additional follow-up may be required. Pregnancies in 
female partners of male patients should also be reported following permission from the partner 
and will be followed in the same manner.  
A Pregnancy Report Form must be submitted to Alkermes (per Section 12.5) immediately, 
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 a SAE, it should be reported following the SAE procedure 
(see Section 12.5). 
8.4.2. 
Prohibited Medications and Supportive Care 
Medications or vaccinations specifically prohibited in the exclusion criteria (Section 7.2) are not 
allowed during the ongoing study. If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the study, discontinuation from study 
therapy or vaccination may be required. The Investigator should discuss any questions about this 
with the ION and Alkermes study teams. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician. If a necessary 
supportive therapy or medication is a prohibited concomitant medication, as described in this 
section, then the patient may continue in the study, coupled with appropriate monitoring by the 
Investigator and upon review and written permission by the ION and Alkermes Medical 
Monitors. 
Live vaccines are not recommended while on study. If the patient has been on a stable dose of 
denosumab for at least 3 months, it is acceptable to continue denosumab or switch to zoledronic 
acid (Zometa®), if possible. Study teams should verify with the local pharmacy that any 
concomitant medications given do not interact with the ALKS 4230 and pembrolizumab agents. 
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. 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study: 
• 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 C1D1 of ALKS 4230), or monoclonal antibody therapy. 
 
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• Prophylactic hematopoietic growth factors. Continued administration of 
erythropoietin may be allowed upon agreement with the ION and Alkermes Medical 
Monitors. 
• Pharmacologic doses of glucocorticoids (≥10 mg of prednisone daily, or equivalent). 
Replacement doses, topical, ophthalmological, and inhalational corticosteroids are 
permitted. Use of glucocorticoids for the purpose of treating immune-mediated AEs is 
permitted but may result in discontinuation from study based on consultation between 
the Investigator and the ION and Alkermes Medical Monitors. A brief course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of 
non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a 
contact allergen) is permitted. 
• Antineoplastic systemic chemotherapy or biological therapy.  
• Chemotherapy not specified in this protocol. 
• Investigational devices or agents other than pembrolizumab and ALKS 4230. 
• Any radiotherapy, including systemically administered radioisotopes.  
NOTE: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the 
Investigator’s discretion.  
• Live vaccines within 30 days prior to the first dose of study drug and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
Bacillus Calmette-Guérin (BCG), intranasal influenza (FluMist®) and typhoid 
vaccine.  
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 [NSAIDs] and/or 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 patient. 
Medroxyprogesterone or megestrol acetate may be given to patients without breast cancer as an 
appetite stimulant, and bisphosphonates or denosumab may be administered to patients with 
bone metastases if started at least 90 days before study entry. 
Additionally, patients may be treated with a histamine type 2 receptor antagonist, 
acetaminophen, meperidine, diphenhydramine, and/or other agents per the Investigator’s 
discretion.  
Because ALKS 4230 is a protein, there are no anticipated metabolic drug-drug interactions. 
Patients who, in the assessment by the Investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. Patients may receive 
other medications that the Investigator deems to be medically necessary. 
The exclusion criteria describe other medications that are prohibited in this study (Section 7.2). 
There are no prohibited therapies during the post-treatment follow-up phase. 
 
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See Section 8.3.4 for details regarding the prior and concomitant medication review. 
 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Study Drug Dose and Administration 
9.1.1. 
ALKS 4230 
A patient is considered enrolled after he or she has completed all screening assessments and 
provided a pretreatment biopsy. Study drug should begin as close as possible to the date of 
enrollment, but no later than 72 hours afterward. On days when pembrolizumab and ALKS 4230 
are both administered, pembrolizumab will be administered first. 
ALKS 4230 will be administered IV as a 30-minute infusion 3 µg/kg daily 5 consecutive days on 
Days 1 through 5 of the first week of each 3-week treatment cycle. 
Infusion for each dosing day of each cycle should begin within ±2 hours of the infusion start 
time for Day 1 of that cycle.
 
 
Premedication with an antipyretic agent (NSAIDs and/or acetaminophen) is required at least 15 
minutes prior to infusion with ALKS 4230 as described in Section 8.4.2. Emergency 
resuscitation equipment should be available. For the first 3 to 6 patients in this study, the first 
2 treatment cycles of ALKS 4230 will be administered in a medical facility with access to 
medical support measures and to an intensive care unit, if needed.  
 
  
Amount of drug administered is based on patients’ body weight as measured at Day 1 of each 
cycle.  
Sites must have written procedures in place detailing the healthcare personnel required to be on 
site during patient dosing, the availability of equipment and medications necessary to treat an 
emergency (should it occur), and the process for transferring a patient to a medical facility if 
necessary. 
Preparation details and procedures are provided in the Pharmacy Manual. 
9.1.2. 
Pembrolizumab 
Pembrolizumab should be administered on Day 1 of each cycle at a dose of 200 mg. Patients will 
receive 1 dose of pembrolizumab Q3W on an outpatient basis. Patients will receive up to 1 year 
of pembrolizumab (17 cycles or 1 year of treatment, whichever occurs later) calculated from the 
date of first dose. There will be no option for retreatment with pembrolizumab alone following 
the completion of combination regimen (a maximum of 17 cycles).  
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion Q3W. 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 of -5 minutes and 
+10 minutes is permitted (ie, infusion time is 30 minutes: -5 minutes/+10 minutes). 
 
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Preparation details and procedures are provided in the Pharmacy Manual. 
9.2. 
Treatment Adherence 
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 supply and 
administration records during the study and/or at the end of the study. 
9.3. 
Randomization/Method of Assigning Patients to Treatment 
Not applicable. There is no randomization in this study. 
9.4. 
Blinding 
Not applicable. The study is open-label. 
9.5. 
Study Drug Dose Delays, Interruptions, and Stopping Rules 
9.5.1. 
Dose Delays 
 
 
 
 
 
 
 
 
In consideration of the prescribing information for pembrolizumab (Keytruda USPI), follow the 
label accordingly for pembrolizumab dose adjustments and stopping rules.  
9.5.2. 
Dose Interruptions and Stopping Rules 
In consideration of the prescribing information for pembrolizumab (Keytruda USPI), follow the 
label accordingly for pembrolizumab dose adjustments and stopping rules. If a patient 
permanently discontinues study therapy, the patient should be discontinued from the study; 
however, every effort should be made to continue monitoring the patient’s disease status by 
radiologic imaging per local standard of care (Section 8.2). 
 
 
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9.5.3. 
Dose Modifications 
 
 
 
Dose reductions of pembrolizumab are not permitted on study. Refer to Section 9.5.1 for 
guidelines on dose delays. 
 
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The decision to continue pembrolizumab or to remove the patient from protocol therapy will be 
made at the discretion of the Investigator and/or the Sponsor and the SRC. 
 
 
 
 
 
 
 
 
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9.5.4.2. 
Events Considered Related to Pembrolizumab 
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These AEs may occur shortly after the first dose or several months after the last dose of 
treatment. Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs. Refer to the Keytruda USPI for dose management of toxicities related to 
pembrolizumab.  
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistical reasons not related to study therapy. Patients should be 
placed back on study therapy within 3 weeks of the scheduled interruption unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient’s 
study record. 
 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
All patients will receive ALKS 4230 and pembrolizumab. 
 Pembrolizumab will be 
externally sourced. 
10.1. 
Study Drug 
10.1.1. 
ALKS 4230 
10.1.2. 
Pembrolizumab 
10.2. 
Packaging and Labeling 
This study is open-label; therefore, the patient, the study site personnel, the Sponsor, Alkermes, 
and other study vendors are not blinded to treatment. Drug identity (name, strength) is included 
in the label text. Random code/disclosure envelopes or lists are not provided. 
10.2.1. 
ALKS 4230 
10.2.2. 
Pembrolizumab 
 
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10.3. 
Storage 
10.3.1. 
ALKS 4230 
The Directions 
for Use will be distributed to the study sites and will provide in-use storage conditions and 
duration of time within which it should be used. 
10.3.2. 
Pembrolizumab 
10.4. 
Accountability 
The Investigator is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug movement records 
during the study and/or at the end of the study. 
Refer to Section 9 for additional study drug reconciliation procedures. 
10.5. 
Handling and Disposal 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration. Discard the drug product vial if visible particles are observed. 
Following completion and verification of accountability logs, all unused and used vials must be 
destroyed. Vials may be destroyed on site according to Good Clinical Practice (GCP) and site 
practice. Alternatively, the Sponsor may arrange for destruction with a third-party vendor 
operating in accordance with GCP and/or Good Manufacturing Practice (GMP), as applicable.  
 
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Details on ALKS 4230 and pembrolizumab ordering and return/destruction may be found in the 
Pharmacy Manual. 
 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Primary Efficacy Endpoint 
The primary objective of this study is to estimate the response rate to ALKS 4230 in combination 
with pembrolizumab in patients with HNSCC who have previously received anti-PD-(L)1 
therapy but who have not achieved a CR. The primary objective will be assessed for the 
following 2 groups:  
• Group 1: Patients with SD, defined as ≥12 weeks of SD per RECIST v1.1 criteria, or 
patients with PR with no further reduction in tumor size or response (ie, PR and not 
improving further) for ≥8 weeks on prior anti-PD-(L)1 therapy 
• Group 2: Patients with PD with no prior response to anti-PD-(L)1 therapy after 
≥8 weeks on anti-PD-1 therapy or patients currently with PD after prior achievement 
of a best response of SD or PR and after ≥8 weeks on anti-PD-(L)1 therapy. 
The primary efficacy endpoint is the rate of new or improved antitumor response (hereafter 
referred to as objective improvement) after the addition of ALKS 4230 treatment in patients 
receiving ongoing anti-PD-1 therapy but who have not achieved a CR. 
Antitumor activity will be measured by radiological assessment compared to screening. 
Antitumor response rate of subsets of patients will be based on disease status (defined by PR, 
SD, or PD based on RECIST v1.1, determined by tumor imaging scans) at screening. 
An objective improvement for patients within Group 1 (Cohorts 1 and 2) is defined as: 
• SD at screening that improves to PR or CR 
• PR at screening that improves to CR 
An objective improvement for patients within Group 2 (Cohorts 3 and 4) is defined as: 
• PD at screening that improves to PR or CR 
Baseline scans must be completed within 28 days before the start of treatment. Scans are to be 
completed according to the time points indicated in the Schedule of Assessments (Table 4). 
Patients whose response converts from PD or SD to PR or from PR to CR will have a 
confirmatory scan for tumor assessments 6 weeks after the response-defining scan. Thereafter, 
timing of tumor assessments will depend on whether or not the patient continues with study drug.   
 
 
 
  
 
 
 
 
 
 
 
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Patients may receive study drug while waiting for confirmation of PD if they are clinically stable 
as defined by the following criteria:  
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG Performance Status  
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
11.2. 
Secondary Efficacy Endpoints 
The secondary objectives are to evaluate the DOR, PFS, TTP, rate of non-progression at 
6 months, and OS of patients with advanced or recurrent HNSCC receiving pembrolizumab plus 
ALKS 4230 and to evaluate the safety and tolerability of pembrolizumab plus ALKS 4230. 
Secondary efficacy endpoints in this study include: 
• DOR, PFS, TTP, rate of non-progression at 6 months, and OS  
• Antitumor response rate of subsets of patients based on disease status (PR, SD, or 
PD) at screening 
• Antitumor activity as measured by radiological assessment compared to screening 
11.3. 
Exploratory Efficacy Endpoints 
The exploratory objectives are:  
• To evaluate whether assessment of pretreatment biopsies from patients who have 
failed to achieve a CR on therapy with anti-PD-(L)1 can identify a subset of patients 
who are likely to respond to the addition of ALKS 4230 
• To evaluate whether a second biopsy, 
, can identify 
changes in tumors predicting response or failure to the addition of ALKS 4230 
• 
 
 
 
 
 
 
 
 
 
 
 
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12. 
ASSESSMENT OF SAFETY 
Safety will be assessed on the basis of: 
• Adverse events 
• Physical examination and ECG findings 
• Vital signs (ie, blood pressure, pulse, respiratory rate, and body temperature)  
• Clinical laboratory parameters (ie, CBC with differential, complete serum chemistry, 
and urinalysis) 
12.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient who has 
been administered a pharmaceutical product. The occurrence, which may or may not have a 
causal relationship with the investigational treatment, may include any clinical or laboratory 
change that does not commonly occur in that patient and is considered clinically significant. 
Illnesses present prior to the patient signing the informed consent form (ICF) are considered to 
be preexisting conditions and are documented on the medical history eCRF. Preexisting 
conditions that worsen during the study are entered on the AE eCRF. 
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 will be 
recorded as such on the eCRFs. 
Progressive disease is not considered an AE. Death due to PD is not considered an SAE (see 
Section 12.5.1). Disease progression and outcome, as assessed by the Investigator, will be 
recorded on the eCRF.  
Pregnancy is not considered an AE, although a patient will be withdrawn from the study if a 
pregnancy occurs. As described in Section 8.4.1, the pregnancy, including a partner’s pregnancy, 
must be reported to Alkermes in an expedited manner similar to an SAE (Section 12.5), and 
additional follow-up may be required.  
12.1.1. 
Events of Clinical Interest 
Selected nonserious and serious adverse events are also known as events of clinical interest 
(ECI) and must be reported within 24 hours to the ION Coordinating Center/Alkermes within 
2 working days. 
For the time period beginning when the consent form is signed through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the patient initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, that occurs to any 
patient, whether or not related to pembrolizumab or ALKS 4230, must be reported within 
24 hours to the ION Coordinating Center/Alkermes within 2 working days. 
 
 
 
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The ECIs for this study include: 
• An elevated aspartate aminotransferase or alanine aminotransferase 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, 
as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing. 
NOTE: These criteria are based upon available regulatory guidance documents. The purpose of 
these criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
12.2. 
Definition of Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• Results in death 
• Is life-threatening. The patient 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 or significant disability/incapacity (eg, a substantial disruption of 
a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
Death secondary to PD is not considered an SAE. Disease progression and outcome, as assessed 
by the Investigator, will be recorded on the eCRF. 
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, 
may jeopardize the patient or patient 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 captured as an AE. 
12.3. 
Relationship to Study Drug 
The assessment of the relationship of study drug to each AE will be reported on the appropriate 
source document (and SAE form, in the event of an SAE) by the Investigator (or designated sub-
Investigator) according to his or her best clinical judgment. The criteria listed in Table 13 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. 
 
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Table 13: 
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 patient 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 
Abbreviation: AE=adverse event. 
12.3.1. 
Toxicity Management for Immune-related Adverse Events Associated with 
Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids, and/or other 
 
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supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, and skin biopsy 
may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
discontinue the ALKS 4230 + pembrolizumab combination regimen and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 14.  
 
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12.3.2. 
Toxicity Management for Infusion Reactions Related to Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 15. 
On days when patients are given combination treatment, institutions should follow the most 
conservative therapy intervention/premedication protocol guidelines. 
 
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12.4. 
Monitoring and Recording of Adverse Events 
Adverse event data collection will begin after a patient signs the ICF and will continue until 
completion of the Safety Follow-up Visit for the main part of the study. Long-term collection of 
AE data is described in Table 5. Any AE or SAE having an onset after the Safety Follow-up 
Visit will not be collected or reported unless the Investigator feels that the event may be related 
to the study drug. 
The Week 3 AE review can be captured via telephone; no visit is required. 
Patients will be instructed by the Investigator or designee to report the occurrence of any AE. All 
volunteered, elicited, and observed AEs are to be recorded on the AE eCRFs. 
The Investigator will assess all AEs regarding any causal relationship to the study drug(s) (see 
Section 12.3), the intensity (severity) of the event, action taken, and patient outcome. For AEs 
not clearly related to either ALKS 4230 or pembrolizumab individually, the most conservative 
approach to treating the event should be used. 
 
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The following criteria should be used to guide the assessment of intensity (severity): 
• Mild: Causes awareness of sign or symptom, but is easily tolerated; does not interfere 
with usual activities 
• Moderate: Causes discomfort enough to interfere with usual activities 
• Severe: Is incapacitating; results in inability to work or perform usual activities 
All AEs will be followed until resolution, until deemed stable by the Investigator, or until the 
patient is deemed by the Investigator to be lost to follow-up. 
Immune-mediated AEs will be documented as such using the immune-mediated AE eCRF. 
For clinical study safety reporting purposes, the most recent version of the ALKS 4230 IB and 
the Keytruda USPI will be used as the reference document to designate event expectedness. 
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 patient withdraws from the study for any reason, 
any ongoing AEs will be followed until resolution, until deemed stable by the Investigator, or 
until the patient is deemed by the Investigator to be lost to follow-up. 
12.5. 
Reporting of Serious Adverse Events and Pregnancy 
All SAEs and Pregnancies must be reported to Syneos Drug Safety immediately, within 
24 hours of discovery, by emailing or faxing the report to the following: 
Attention: Syneos Drug Safety 
FAX Number: +1 (877) 464-7787 
Phone Number: +1 (877) 462-0134 
Email: incdrugsafety@incresearch.com 
 
Attention: Drug Safety and Pharmacovigilance 
FAX Number: +1 (617) 494-5202 
The written report for SAEs should be submitted on the SAE form provided for this purpose. The 
SAE report must include the Investigator’s opinion as to whether the event is 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. 
The written report for pregnancies in female patients and in female partners of male patients 
should be submitted on the Pregnancy Report Form provided for this purpose. 
12.5.1. 
Protocol-specific Exemptions to Serious Adverse Event Reporting 
Any event that indicates disease progression will not be reported to Alkermes as described in this 
section, including death secondary to disease progression, unless there is evidence suggesting a 
causal relationship between the drug and the event. If there is such a causal relationship, then the 
event will be submitted to the ION Coordinating Center/Alkermes within 24 hours. 
 
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The ION Coordinating Center/Alkermes will monitor aggregated efficacy endpoint events and 
safety data to ensure the safety of the patients in the study. Any serious suspected events that, 
upon review, are not determined to be progression of the cancer under study will be forwarded to 
the ION Coordinating Center/Alkermes within 24 hours. 
12.5.2. 
Reporting of Pregnancy Events 
Although pregnancy and lactation are not considered AEs under this protocol, it is the 
responsibility of Investigators or their designees to report any pregnancy or lactation in a patient 
(spontaneously reported to them) that occurs during the study. 
Pregnancies and lactations that occur from the time the patient is enrolled (including pregnancies 
in the female partners of male patients) through 120 days following cessation of study product, 
or 30 days following cessation of treatment if the patient initiates new anticancer therapy, 
whichever is earlier, must be reported by the Investigator. All reported pregnancies must be 
followed to the completion or termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage and stillbirth must be reported as SAEs (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the ION Coordinating Center or Alkermes. 
 
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13. 
STATISTICS 
13.1. 
Sample Size Considerations 
This study plans to enroll 
 efficacy evaluable patients in Groups 1 and 2, 
 
In the long-term follow-up analysis of the KEYNOTE-012 trial of single agent pembrolizumab, 
which was conducted in 192 patients with HNSCC, the objective improvement rate was 18% 
(95% CI, 13% to 24%) (Mehra et al, 2018). Among the subset of patients achieving a response, 
the median time to objective improvement was 2 months (range, 2 to 17 months). 
 
 
 
 
 
 
 
 
 
 
 
 
13.2. 
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 for 
continuous variables, and number [%] of patients in each category for categorical variables) will 
be provided by group for all variables. Time-to-event variables will be summarized by Kaplan-
Meier plots, medians, and ranges. The data will be tabulated and analyzed with respect to patient 
enrollment and disposition, demographic and baseline characteristics, prior and concomitant 
medications, efficacy, and safety measures.  
Source data for the summary tables and statistical analyses will be presented as patient data 
listings. 
All statistical tests and CIs, unless stated otherwise, will be 2-sided and will be set at α=0.05. 
13.2.1. 
Study Populations 
13.2.1.1. Efficacy Evaluable Population 
All patients who received at least 1 dose of both study drugs will be included in the analysis of 
efficacy, regardless of the duration of treatment. The Efficacy Evaluable populations will be 
characterized by groups (Group 1 and Group 2) and overall for analysis of all efficacy endpoints. 


 
 
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Protocol ION-01-ALKS 4230 
 
CONFIDENTIAL 
13.2.1.2. Safety Population 
The Safety population, defined as all patients who receive at least 1 dose of investigational 
combination treatment regimen, will be used in the safety analyses, regardless of the duration of 
treatment. The data will be presented by treatment arm and overall. 
13.3. 
Demographics and Baseline Data 
Baseline is defined as the last value prior to the first dose of study treatment administration.  
Demographics and baseline characteristics such as gender, age, race, weight, vital signs, and 
clinical laboratory data will be summarized with descriptive statistics. 
13.4. 
Efficacy Analyses 
Response to treatment will be evaluated using both RECIST v1.1 and immune-related response 
criteria (irRC). For patients with objectively measurable disease, response to therapy, DOR, PFS, 
and OS will be calculated.  
13.4.1. 
Primary Efficacy Endpoints Analysis 
Primary efficacy analysis will be evaluated in patients in the Efficacy Evaluable population for 
each group separately and overall. The objective improvement rate (as defined in Section 11.1) 
after continued anti-PD-1 therapy with ALKS 4230 will be summarized by group (Group 1 and 
Group 2) separately and overall with descriptive statistics. The analysis of objective response 
rate using an exact binomial test will also be conducted separately for each group. 
The 95% CI on the objective improvement rate will be reported. Similar approaches will also be 
applied to the overall population. 
13.4.2. 
Secondary Efficacy Analysis 
Secondary efficacy analysis will be evaluated on the Efficacy Evaluable patients.  
DOR and TTP will be calculated and summarized by group and overall. Patients with missing 
response data will be considered non-responders and excluded from the DOR analysis. PFS and 
OS curves will be plotted by group and overall using the Kaplan-Meier approach. The median 
survival time (if applicable) and its 95% CI for PFS and OS will be reported. The PFS and OS 
rate at 6 and 12 months will be estimated using the Kaplan-Meier approach. 
The objective response rate will be summarized for each of the 4 cohorts. 
The percentage change from baseline in target lesions will be summarized by group and overall. 
 
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13.5. 
Safety and Tolerability Analyses 
Safety will be evaluated based on the occurrence of AEs, vital signs, results of clinical laboratory 
tests, and ECG findings. Reported AE terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®) version 21 preferred terms and system organ classes. 
Treatment-emergent AEs (TEAEs) are defined as any AE that begins on or after the first 
administration of the study drug. Adverse event severity will be graded according to the CTCAE 
v5.0 and terms recorded on the CRFs will be mapped to preferred terms using the most recent 
version of the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
All AEs will be listed. The incidence of TEAEs will be summarized for each group and overall, 
by severity, and by relationship to study drug as assessed by the Investigator. The summary 
tables will include the number and percentage of patients with TEAEs overall, by system organ 
class, and by preferred terms within each system organ class. Similar tables will be prepared for 
SAEs, TEAEs leading to discontinuation, as well as additional categories of AEs as defined in 
the SAP. 
Results of clinical laboratory tests will be summarized by visit for the absolute value and for 
change from baseline. Tables showing the shift from baseline will also be presented. 
ECG findings will be listed. 
Concomitant medications will be categorized and presented using the World Health Organization 
Anatomical Therapeutic Chemical (WHO-ATC) drug classification system. 
 
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by an Alkermes Monitor or designee.  
14.2. 
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, or an institutional review board (IRB)/independent ethics committee (IEC) may visit 
the site to perform audits or inspections, including the drug storage area, study drug stocks, drug 
accountability records, patient charts and source documents, and other records relative to study 
conduct. The purpose of an Alkermes audit or inspection is to systematically and independently 
examine study-related activities and documents (eg, laboratory reports, X-rays, workbooks, 
patients’ medical records) to determine whether these activities were conducted, and data 
recorded, analyzed and accurately reported, according to the protocol, GCP guidelines of the 
International Council on Harmonisation (ICH), and any applicable regulatory requirements.  
The Investigator should contact Alkermes immediately if contacted by a regulatory agency 
regarding an inspection. 
14.3. 
Institutional Review Board/Independent Ethics Committee 
The Investigator must obtain IRB/IEC approval for the investigation. Initial and subsequent 
IRB/IEC approvals, as well as all materials approved by the IRB/IEC for this study, including 
the patient consent form and recruitment materials, must be maintained by the Investigator and 
made available for inspection. 
 
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15. 
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 site should have processes in place for 
data review and quality control. Alkermes may also conduct a quality assurance audit. Please see 
Section 14.2 for details regarding the audit process. 
15.1. 
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 prior to review by the Alkermes Monitor or designated representative. 
The Alkermes Monitor or designated representative will review all source records on-site and 
compare them to the data collected on the eCRF.  
15.2. 
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 or IEC under an appropriate understanding of confidentiality with 
such board. Please refer to the Clinical Study Agreement (CSA) for details. 
 
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16. 
ETHICAL CONSIDERATIONS 
16.1. 
Ethics Review 
The clinical site’s IRB/IEC must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB/IEC prior to enrolling patients into the study; written 
approval from the committee must be received by Alkermes before study drug will be released to 
the Investigator. The protocol must be reapproved by the IRB/IEC 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/IEC 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/IEC will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
16.2. 
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. Good Clinical Practice is an international ethical and 
scientific quality standard used for designing, conducting, recording, and reporting studies 
involving the participation of human patients. Alkermes is committed to complying with this 
standard to provide assurance that the rights, safety, and well-being of study patients will be 
protected, consistent with the principles having their origin in the Declaration of Helsinki.  
16.3. 
Written Informed Consent 
The Investigator (or authorized designee) at each center will ensure that the patient (or the 
patient’s legal representative) is given full and adequate oral and written information about the 
nature, purpose, and potential risks and benefits of the study. Each prospective patient 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 patient and must not include any language that waives the 
patient’s legal rights. Prospective patients must also be informed of their right to withdraw 
consent without prejudice at any time during the study. If the patient chooses to participate, he or 
she must sign the ICF before any study-specific procedures are conducted.  
All patients will be informed of their rights to privacy and will be made aware that the study data 
will be submitted to Alkermes, ION, the IRB, the contract research organization (CRO), if 
applicable, and to regulatory authorities for review and evaluation for the duration of the study 
and until the project has been approved for marketing or is withdrawn from investigation. They 
will also be informed that the Study 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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CONFIDENTIAL 
The time that informed consent is obtained must be documented. The Investigator must maintain 
the original signed ICF in the patient’s source documents. A copy of the signed ICF must be 
given to the patient. 
 
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CONFIDENTIAL 
17. 
DATA HANDLING AND RECORDKEEPING 
An overview of study data handling and recordkeeping procedures and restrictions is provided in 
the subsequent sections; please refer to the CSA for further details. 
17.1. 
Data Capture 
As stated in Section 15.1, 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 (EDC) system maintains a full audit trail.  
A copy of all laboratory reports will remain with the source documents at the study site. All 
electronic source data collected outside of the eCRF, such as e-diaries or centrally reviewed 
patient data will be transferred directly to the EDC or to Alkermes for incorporation into the final 
datasets. 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 
will be recorded as such on the eCRFs.  
Adverse events will be coded using MedDRA version 21. Concomitant medications will be 
categorized using the WHO-ATC drug classification system. 
17.2. 
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, 
patient charts or electronic medical records and source documents, and other records relative to 
study conduct. 
17.3. 
Retention of Records 
Retention and storage of all essential clinical study documents shall be governed by the terms 
and conditions of the site’s CSA and in accordance with ICH guidelines/local regulatory 
requirements as follows: 
Essential documents should be retained 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. 
Patients’ medical files should be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
 
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18. 
REFERENCES 
Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet. 
2008;371(9625):1695-1709. doi: 10.1016/s0140-6736(08)60728-x. 
Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for Platinum- and Cetuximab-Refractory 
Head and Neck Cancer: Results From a Single-Arm, Phase II Study. J Clin Oncol. 
2017;35(14):1542-1549. doi: 10.1200/jco.2016.70.1524. 
Cohen EE, Harrington KJ, Le Tourneau C, et al. Pembrolizumab vs Standard of Care for 
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Phase 3 KEYNOTE-040 
Trial WURL- https://hostedvl142.quosavl.com/qb/doc/b327d032bd7ddb0c9d3cc710be0fd801. 
Ann Oncol. 2017:28(suppl_25) 628. 
Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell 
carcinoma of the head and neck. J Clin Oncol. 2006;24(17):2644-2652. doi: 
10.1200/jco.2005.05.3348. 
Gregoire V, Lefebvre JL, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: 
EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol. 2010;21 Suppl 5:v184-186. doi: 10.1093/annonc/mdq185. 
Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence 
across five continents: defining priorities to reduce cancer disparities in different geographic 
regions of the world. J Clin Oncol. 2006;24(14):2137-2150. doi: 10.1200/jco.2005.05.2308. 
Keytruda US Prescribing Information. Whitehouse, NJ: Merck & Co, Inc. 
Larkins E, Blumenthal GM, Yuan W, et al. FDA Approval Summary: Pembrolizumab for the 
Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease 
Progression on or After Platinum-Containing Chemotherapy. Oncologist. 2017;22(7):873-878. 
doi: 10.1634/theoncologist.2016-0496. 
Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol. 
2005;16 Suppl 6:vi7-vi12. doi: 10.1093/annonc/mdi452. 
Losey HC, Lopes JE, Dean RL, Huff MR, Moroso RA, Alvarez JC. Abstract 591: Efficacy of 
ALKS 4230, a novel immunotherapeutic agent, in murine syngeneic tumor models alone and in 
combination with immune checkpoint inhibitors. Cancer Res. 2017;77 WURL- 
https://hostedvl142.quosavl.com/qb/doc/ad38aa22b5a5ad110395a23e6271fb0a(13 
Supplement):591-591. 
Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in 
recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term 
follow-up in KEYNOTE-012. Br J Cancer. 2018;119(2):153-159. doi: 10.1038/s41416-018-
0131-9. 
 
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National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: 
Head and Neck Cancers. 2016. 
Rothenberg SM, Ellisen LW. The molecular pathogenesis of head and neck squamous cell 
carcinoma. J Clin Invest. 2012;122(6):1951-1957. 
Rousseau A, Badoual C. Head and Neck: Squamous cell carcinoma: an overview. =. Atlas of 
Genetics and Cytogenetics in Oncology and Haematology. 2012. 
Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for 
treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-
012): an open-label, multicentre, phase 1b trial. Lancet. 2016;17(7):956-965. doi: 
10.1016/s1470-2045(16)30066-3. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA. 2016;66(1):7-30. doi: 
10.3322/caac.21332. 
Specenier PM, Vermorken JD. Recurrent head and neck cancer: current treatment and future 
prospects. Expert Rev Anticancer Ther. 2008;8(3):375-391. doi: 10.1586/14737140.8.3.375. 
Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J. Overview of the efficacy of cetuximab 
in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who 
previously failed platinum-based therapies. Cancer. 2008;112(12):2710-2719. doi: 
10.1002/cncr.23442. 
  
 
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SAP_001.pdf: 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
ION-01-ALKS 4230 
NCT04144517 
 
Study Title: 
A Phase 2 Study of ALKS 4230 in Combination With Anti-PD-
1(Pembrolizumab) in Patients With Advanced or Recurrent Head and 
Neck Squamous Cell Cancer Currently on Treatment With Anti-PD-
(L)1 Without Having Achieved a Complete Remission  
Document Status: 
 1.0 
Document Date: 
 18 Mar 2021 
Based on: 
 Study protocol Version 1 (dated 29 Oct 2018) 
 
 
 
 
 
 
CONFIDENTIAL 
Information and data in this document 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. 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF TABLES .................................................................................................................. 4 
LIST OF FIGURES ................................................................................................................. 4 
ABBREVIATIONS ................................................................................................................. 5 
1. 
INTRODUCTION ................................................................................................. 9 
1.1. 
Study Objectives ................................................................................................... 9 
1.1.1. 
Primary Objective.................................................................................................. 9 
1.1.2. 
Secondary Objectives ............................................................................................ 9 
1.1.3. 
Exploratory Objectives .......................................................................................... 9 
1.2. 
Summary of the Study Design.............................................................................. 10 
1.3. 
Study Endpoints .................................................................................................. 12 
1.3.1. 
Primary Efficacy Endpoint................................................................................... 12 
1.3.2. 
Secondary Efficacy Endpoints.............................................................................. 14 
1.3.3. 
Exploratory Endpoints ......................................................................................... 14 
2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION .................... 15 
3. 
DATA ANALYSIS ............................................................................................. 15 
3.1. 
General Statistical Methodology .......................................................................... 15 
3.2. 
Definitions of Analysis Populations ..................................................................... 15 
3.2.1. 
Efficacy Evaluable Population ............................................................................. 15 
3.2.2. 
Safety Population ................................................................................................ 16 
3.3. 
Disposition .......................................................................................................... 16 
3.4. 
Protocol Deviations ............................................................................................. 16 
3.5. 
Demographics and Baseline Characteristics .......................................................... 17 
3.6. 
Cancer Disease History........................................................................................ 17 
3.7. 
Medical History................................................................................................... 17 
3.8. 
Prior Cancer Related Therapies ............................................................................ 17 
3.9. 
Prior and Concomitant Medications ..................................................................... 17 
3.10. 
Extent of Exposure .............................................................................................. 18 
3.11. 
Efficacy Analyses................................................................................................ 18 
3.11.1. 
General Considerations ........................................................................................ 18 
3.11.2. 
Efficacy Analysis for the Primary Efficacy Endpoint ............................................ 19 
3.11.3. 
Efficacy Analysis for the Secondary Efficacy Endpoints ....................................... 19 


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 21 
3.13. 
Safety Analysis ................................................................................................... 21 
3.13.1. 
General Considerations ........................................................................................ 21 
3.13.2. 
Adverse Events ................................................................................................... 21 
3.13.3. 
Death .................................................................................................................. 22 
3.13.4. 
Clinical Laboratory Parameters ............................................................................ 23 
3.13.5. 
Vital Signs .......................................................................................................... 24 
3.13.6. 
Electrocardiograms (ECG) ................................................................................... 25 
3.13.7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status....................... 25 
4. 
INTERIM ANALYSES ....................................................................................... 26 
5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ....................................................................................................... 27 
5.1. 
Revisions and/or clarification of definitions in SAP .............................................. 27 
6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ......... 28 
6.1. 
Analysis Visit Windows ...................................................................................... 28 
6.2. 
Efficacy Data Handling........................................................................................ 28 
6.2.1. 
Censoring Rules for Duration of Response (DOR) ................................................ 29 
6.2.2. 
Censoring Rules for Progression Free Survival (PFS) ........................................... 30 
6.3. 
Safety Data Handling........................................................................................... 31 
6.4. 
Handling of Partial Dates of Concomitant Medication........................................... 31 
7. 
GENERAL STATISTICAL METHODOLOGY ................................................... 32 
7.1. 
Reporting Precision ............................................................................................. 32 
8. 
PROGRAMMING SPECIFICATIONS ................................................................ 33 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS)......................................... 34 
10. 
REFERENCES.................................................................................................... 35 
 


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LIST OF TABLES 
Table 1: 
Clinical Laboratory Assessments.......................................................................... 24 
Table 2: 
Eastern Cooperative Oncology Group Performance Status .................................... 25 
Table 3: 
Censoring Rules for Overall Survival (OS) ........................................................... 28 
Table 4: 
Censoring Rules for Duration of Response ........................................................... 29 
Table 5: 
Censoring Rules for Progression Free Survival ..................................................... 30 
Table 6: 
Degree of Precision ............................................................................................. 32 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic 1 ................................................................................... 12 
Figure 2: 
Study Design Schematic 2 ................................................................................... 12 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AC 
Absolute Counts 
ADA 
Anti-Drug Antibodies  
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC∞ 
Area Under the Curve from Time Zero to Infinity 
AUC24H 
Area Under the Curve from Time Zero to 24 Hours Post dose 
AUCLAST 
Area Under the Curve from Time Zero to the Last Observed Quantifiable 
Concentration 
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 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough Concentrations 
DLT 
Dose-Limiting Toxicity 
DCR 
Disease Control Rate 


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Abbreviation 
Definition 
DOR 
Duration of Response 
ECG 
Standard 12-Lead Electrocardiogram 
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 
HNSCC 
Squamous Cell Carcinoma of the Head and Neck 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IFN 
Interferon 
IL-2 
Interleukin-2 
IL-2R 
Interleukin-2 Receptor 
INR 
International Normalized Ratio 
ir 
Immune-Related 
irORR 
Immune-Response Overall Response Rate 
irRC 
Immune-Related Response Criteria 
IV 
Intravenous or Intravenously 
LDH 
Lactate Dehydrogenase 
λz 
Terminal Elimination Rate Constant 
MAX 
Maximum 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MIN 
Minimum 
MTD 
Maximum Tolerated Dose 


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Abbreviation 
Definition 
NCI 
National Cancer Institute 
NK 
Natural Killer [Cells] 
N/A 
Not Applicable 
ORR 
Overall Response Rate 
PCS 
Potentially Clinically Significant 
PD 
Progressive Disease 
PD-1 
Programmed Death Receptor-1 
PD-L1 
Programmed Death Ligand-1 
PFS 
Progression-Free Survival 
PR 
Partial Response 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
Q3W 
Every 3 Weeks 
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 
iRECIST 
Immune 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 
SD 
Stable Disease 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 


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Abbreviation 
Definition 
T1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
Table, Listing and Figure 
TMAX 
Time to Cmax 
TNF 
Tumor Necrosis Factor 
TCD8, MAX 
Time to Maximum RCD8 
TNK, MAX 
Time to Maximum RNK 
TTREGS 
Regulatory T Cells 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
VS 
Versus 
VSS 
Steady-State Volume of Distribution 
VZ 
Terminal Volume of Distribution 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and data presentation to be 
used for analyzing and reporting efficacy and safety data for study ION-01-ALKS 4230. This 
document has been prepared based on the Alkermes ION-01-ALKS 4230 study protocol (dated 
29 Oct 2018).  
1.1. 
Study Objectives 
1.1.1. 
Primary Objective 
The primary objective of this study is to estimate the response rate to ALKS 4230 in combination 
with pembrolizumab in patients with Squamous Cell Carcinoma of the Head and Neck (HNSCC) 
who have previously received anti-programmed cell death protein 1 (anti-PD-1) or anti-
programmed cell death ligand-1 (anti-PD-L1) (henceforth referred to as PD-[L]1) therapy but 
who have not achieved a complete remission (CR). The primary objective will be assessed for 
the following 2 groups: 
  
• Group 1: Patients with stable disease (SD), defined as ≥12 weeks of SD per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, or patients with partical 
response (PR) with no further reduction in tumor size or response (ie, PR and not 
improving further) for ≥8 weeks on prior anti-PD-(L)1 therapy  
• Group 2: Patients with PD (progressive disease) with no prior response to anti-PD-(L)1 
therapy after ≥8 weeks on anti-PD-1 therapy or patients currently with PD after prior 
achievement of a best response of SD or PR and after ≥8 weeks on anti-PD-(L)1 therapy 
 
1.1.2. 
Secondary Objectives 
• To evaluate the duration of response (DOR), progression-free survival (PFS), time to 
progression (TTP), and overall survival (OS) of patients with advanced or recurrent 
HNSCC receiving pembrolizumab plus ALKS 4230 
• To evaluate the safety and tolerability of pembrolizumab plus ALKS 4230 
 
1.1.3. 
Exploratory Objectives  
• To evaluate whether assessment of pretreatment biopsies from patients who have failed to 
achieve a CR on therapy with anti-PD-(L)1 can identify a subset of patients who are 
likely to respond to the addition of ALKS 4230 
 
 
 
• To evaluate whether a second biopsy,
 
 will predict response or failure to the addition of ALKS 4230 
 
 


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1.2. 
Summary of the Study Design 
The study will assess the antitumor efficacy of ALKS 4230 in combination with pembrolizumab 
in patients with advanced, recurrent, and/or HNSCC on treatment with an anti-PD-(L)1 antibody 
(pembrolizumab or nivolumab) without having achieved a CR. 
The study is a multi-center, Phase 2, open-label therapy study in collaboration with ION. Patients 
must have received anti-PD-(L)1 therapy prior to enrollment into the study. After enrollment in 
the study, ALKS 4230 with pembrolizumab will be administered to 4 cohorts of patients with 
advanced, recurrent, and/or metastatic HNSCC who have received anti-PD-(L)1 therapy whose 
current response is as follows:  
• Cohort 1: SD, defined as ≥12 weeks of SD per RECIST criteria 
• Cohort 2: PR with no further reduction in tumor size or response for ≥8 weeks (ie, PR 
and not improving further)  
• Cohort 3: PD with no prior response to anti-PD-(L)1 therapy after ≥8 weeks on anti-
PD-(L)1  
• Cohort 4: Current PD after prior achievement of best response of SD or PR and after 
≥8 weeks on anti-PD-(L)1 therapy  
 
Patients will be administered the combination of ALKS 4230 and pembrolizumab. For 
simplification, the 4 cohorts of patients will be combined into 2 arms:  
• Group 1 will consist of all patients with current SD or PR (Cohorts 1 and 2) who are 
not progressing or further demonstrating reductions in tumor size.  
• Group 2 will consist of patients with PD (Cohorts 3 and 4).  
 
Baseline tumor biopsy will be required at the time of study entry after screening procedures have 
been completed and prior to first administration of combination regimen to assess each patient’s 
tumor characteristics in an effort to identify patients with tumors that may have limited 
pembrolizumab efficacy or potential response to anti-PD-1/ALKS 4230 combination. Tumors 
will be assessed for quantity and character of tumor-infiltrating T cells and other leukocytes, and 
for quantitative assessment of PD-L1 expression, gene signatures that correlate with response or 
lack of response 
 
  


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Patients will also have a post-treatment (second) biopsy at C1D12, or at any time from C1D8 
through C1D19, to assess whether the addition of ALKS 4230 to the treatment regimen alters the 
TME and what changes on therapy (immunopharmacodynamics) predispose to responses to the 
combination.  
The study plans to enroll 
 evaluable patients for Groups 1 and 2, 
 The 
number of patients enrolled into each cohort within each group will be determined at the time of 
enrollment, based on the patient’s response to previous treatment. It will be at the discretion of 
Alkermes and ION to expand a particular cohort of interest 
 
.  
Pembrolizumab will be administered according to the standard regimen of 200 mg flat dose IV 
Q3W. ALKS 4230 will be administered IV at a daily dose of 3 μg/kg, given daily on 5 
consecutive days on Days 1 through 5 of the first week of each 3-week treatment cycle.  
ALKS 4230 may be continued until toxicity develops. If a toxicity attributed to ALKS 4230 
occurs, dosing for both pembrolizumab and ALKS 4230 will be held. After recovery from an AE 
that meets dose hold criteria, the patient may resume at full dose of pembrolizumab and full or 
reduced dose of ALKS 4230 in subsequent cycles with consultation from the Medical Monitor or 
may discontinue from the study. 
 
 
  
Patients with tumors who respond to treatment will continue until the following:  
• Confirmed progression occurs (upon agreement with the ION and Alkermes Medical 
Monitors, patients tolerating therapy and receiving clinical benefit may be allowed to 
stay on study for up to 1 year)  
• Until unacceptable toxicity occurs  
• Other criteria for discontinuation occur  
 
Safety and tolerability will be assessed and reported using standard Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 criteria. Safety will be monitored by the study 
Principal Investigator (PI), participating site PIs, the ION Coordinating Center PI and staff, and 
representatives from Alkermes. Details pertaining to the Safety Review Committee (SRC), 
including participants, frequency of meetings, and criteria that would trigger ad hoc meetings, 
are described in the SRC Charter.  
If the unacceptable AEs (defined in Section 12.2 of protocol) observed are typical of known 
pembrolizumab and/or ALKS 4230 toxicities, the following will be considered: (1) revising the 
protocol eligibility requirements to decrease the likelihood of toxicities, (2) modifying the dose 
or schedule, or (3) allowing the study to proceed as designed assuming that patients in this study 
will have fatal diseases and few other treatment options. The risk/benefit ratio will need to be 
evaluated in this situation.  
If unexpected, unacceptable AEs are considered to be related to concurrent administration of 
ALKS 4230 and pembrolizumab, the PI, participating site PIs, the ION Coordinating Center PI 
and staff, and representatives from Alkermes will consider revising the protocol eligibility 


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requirements to decrease the likelihood of toxicities or may consider allowing the study to 
proceed as designed given the risk/benefit ratio for this population.  
Study design schematics are provided in Figure 1 and Figure 2. 
Figure 1: 
Study Design Schematic 1 
 
 
Abbreviations: CR=complete remission; HNSCC=squamous cell carcinoma of the head and neck; PD=progressive 
disease; PD-(L)1=programmed cell death ligand-1; PR=partial response; SD=stable disease; Q3W=every 3 weeks  
Figure 2: 
Study Design Schematic 2 
 
Abbreviations: IV=intravenous; Q3W=every 3 weeks 
Note: Pembrolizumab regimen is as follows: 200 mg once Q3W by IV infusion;ALKS 4230 regimen is as follows: 3 
μg/kg, given daily on 5 consecutive days on Days 1 through 5 of the first week of each 3-week treatment cycle.  
 
1.3. 
Study Endpoints 
1.3.1. 
Primary Efficacy Endpoint 
 


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The primary objective of this study is to estimate the response rate to ALKS 4230 in combination 
with pembrolizumab in patients with HNSCC who have previously received anti-PD-(L)1 
therapy but who have not achieved a CR. The primary objective will be assessed for the 
following 2 groups:  
 
• Group 1: Patients with SD, defined as ≥12 weeks of SD per RECIST v1.1 criteria, or 
patients with PR with no further reduction in tumor size or response (ie, PR and not 
improving further) for ≥8 weeks on prior anti-PD-(L)1 therapy  
• Group 2: Patients with PD with no prior response to anti-PD-(L)1 therapy after ≥8 
weeks on anti-PD-1 therapy or patients currently with PD after prior achievement of a 
best response of SD or PR and after ≥8 weeks on anti-PD-(L)1 therapy.  
 
The primary efficacy endpoint is the rate of new or improved antitumor response (hereafter 
referred to as objective improvement) after the addition of ALKS 4230 treatment in patients 
receiving ongoing anti-PD-1 therapy but who have not achieved a CR.  
Antitumor activity will be measured by radiological assessment compared to screening. 
Antitumor response rate of subsets of patients will be based on disease status (defined by PR, 
SD, or PD based on RECIST v1.1, determined by tumor imaging scans) at screening.  
An objective improvement for patients within Group 1 (Cohorts 1 and 2) is defined as:  
 
• SD at screening that improves to PR or CR  
• PR at screening that improves to CR  
 
An objective improvement for patients within Group 2 (Cohorts 3 and 4) is defined as:  
• PD at screening that improves to PR or CR  
 
Baseline scans must be completed within 28 days before the start of treatment. Scans are to be 
completed according to the time points indicated in the Schedule of Assessments (Table 4 in the 
protocol). Patients whose response converts from PD or SD to PR or from PR to CR will have a 
confirmatory scan for tumor assessments 6 weeks after the response-defining scan. Thereafter, 
timing of tumor assessments will depend on whether or not the patient continues with study 
drugs.  
 
 
 
  
 
 
 
 
 
 
 
 
  


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Patients may receive study drug while waiting for confirmation of PD if they are clinically stable 
as defined by the following criteria:  
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression  
• No decline in ECOG Performance Status  
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention  
 
1.3.2. 
Secondary Efficacy Endpoints  
The secondary objectives are to evaluate the DOR, PFS, TTP, rate of non-progression at 6 
months, and OS of patients with advanced or recurrent HNSCC receiving pembrolizumab plus 
ALKS 4230 and to evaluate the safety and tolerability of pembrolizumab plus ALKS 4230.  
Secondary efficacy endpoints in this study include:  
• DOR, PFS, TTP, rate of non-progression at 6 months, and OS  
• Antitumor response rate of subsets of patients based on disease status (PR, SD, or PD) 
at screening  
• Antitumor activity as measured by radiological assessment compared to screening  
 
1.3.3. 
Exploratory Endpoints 
The exploratory objectives are:  
• To evaluate whether assessment of pretreatment biopsies from patients who have failed 
to achieve a CR on therapy with anti-PD-(L)1 can identify a subset of patients who are 
likely to respond to the addition of ALKS 4230  
• To evaluate whether a second biopsy, 
, can identify 
changes in tumors predicting response or failure to the addition of ALKS 4230  
 


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2. 
SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION 
This study plans to enroll 
 efficacy evaluable patients in Groups 1 and 2, 
. 
In the long-term follow-up analysis of the KEYNOTE-012 trial of single agent pembrolizumab, 
which was conducted in 192 patients with HNSCC, the objective improvement rate was 18% 
(95% CI, 13% to 24%) (Mehra et al, 2018i). Among the subset of patients achieving a response, 
the median time to objective improvement was 2 months (range: 2 to 17 months). 
 
 
 
 
 
  
 
 
 
 
 
  
3. 
DATA ANALYSIS 
3.1. 
General Statistical Methodology 
Baseline for efficacy or safety analysis is defined as the last non-missing assessment before the 
first dose of study drug in ION-01-ALKS 4230 study on Day 1, and it will be used for all 
efficacy and safety analysis unless specified otherwise.  
In general, summary statistics (n, mean, standard deviation, median, minimum and maximum for 
continuous variables, and number [%] of patients in each category for categorical variables) will 
be provided by group for all variables. Time-to-event variables will be summarized by Kaplan- 
Meier plots, medians, and ranges. The data will be tabulated and analyzed with respect to patient 
enrollment and disposition, demographic and baseline characteristics, prior and concomitant 
medications, efficacy, and safety measures. Source data for the summary tables and statistical 
analyses will be presented as patient data listings. All statistical tests and CIs, unless stated 
otherwise, will be 2-sided and will be set at α=0.05.  
3.2. 
Definitions of Analysis Populations 
3.2.1. 
Efficacy Evaluable Population  
The Efficacy Evaluable Population will include all patients who have received at least 1 dose of 
both study drugs and have minimum of one post-baseline scan. The Efficacy Evaluable 
Population will be characterized by groups (Group 1 and Group 2) and overall for analysis of all 
efficacy endpoints. 


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3.2.2. 
Safety Population  
The Safety Population is defined as all patients who receive at least 1 dose of investigational 
combination treatment regimen, will be used in the safety analyses, regardless of the duration of 
treatment. The data will be presented by groups and overall. The Safety Population will be used 
for safety analyses as well as for demographics, and baseline characteristics. 
 
3.3. 
Disposition 
The number and percentage of patients in the efficacy evaluable population, patients in the safety 
population, patients who completed the study, and patients who were prematurely terminated 
from the study will be summarized. 
According to study protocol Section 7.3, a patient may be discontinued from the study at any 
time if the patient or Investigatory determines that it is not in the best interest of the patient to 
continue participation.  
For patients who discontinued from the study, the reasons for discontinuation will be 
summarized for the following categories: 
• Adverse event 
• Disease progression 
• Loss to follow-up 
• Withdrawal of consent 
• Non-Compliance with study drug 
• Physician Decision  
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• Other 
Patients’ completion/discontinuation status will be listed, including patient identifier, informed 
consent date, date of completion/discontinuation and, for those who discontinued early, the 
specific reason(s) for discontinuation. 
3.4. 
Protocol Deviations 
Major protocol deviations will be summarized and listed by each category.  All protocol 
deviations identified according to study entry criteria and during treatment will be listed. 


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3.5. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the Safety Population. 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 to <25 kg/m2 ; 
overweight: 25 to <30 kg/m2; obese: ≥30 kg/m2), and ECOG performance status (0, 1, 2, 3, 4, or 
5) 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 date 
will be provided in listings. 
 
3.6. 
Cancer Disease History 
Cancer disease history will be summarized. The number and percentage of patients 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. 
3.7. 
Medical History  
Reported medical history terms will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0 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. 
3.8. 
Prior Cancer Related Therapies 
A frequency tabulation of the number of patients with previous cancer-related surgery, radiation 
therapy, and systemic therapy including line of therapy will be provided. In addition, tabulation 
will be provided by location of radiation therapy and type of previous systemic therapy. 
3.9. 
Prior and Concomitant Medications 
A prior medication is defined as any medication taken with an end date prior to the first dose of 
study drug. A prior regimen can contain more than one prior medications. A concomitant 
medication is defined as any medication (1) that started  before the first dose of study drug and 
was continuing at the time of the first dose of study drug, or (2) started on or after the date of the 
first dose of study drug and continued up to 30 days after the patient’s last dose of study drug.  
The number and percentage of patients who have taken prior or concomitant medications will be 
summarized using the WHO-ATC generic drug name dictionary (version: March 2016 or higher) 
for the Safety population. 


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For the summary table, if a subject has taken a concomitant medication more than once, the 
subject will be counted only once for that medication. A patient who reports the use of two or 
more medications with same start date will be counted only once in the summary of "Any 
Concomitant Medication." Similar rules will apply to prior medications as well. 
The concomitant medication will be reviewed by medical team to identify the anti-cancer 
therapy treatment during the study. 
All reported medications (including prior medications and concomitant medication) will be 
included in listing. 
3.10. 
Extent of Exposure 
For each study drug, the ALKS 4230 and the pembrolizumab administration profile will be 
summarized with respect to treatment duration, total number of ALKS 4230 and pembrolizumab 
infusions, cumulative  dose (µg/kg) of ALKS 4230 and pembrolizumab (mg) administered, and 
number of cycles.   
The following items will be summarized for both ALKS 4230 and pembrolizumab: 
       Duration of Exposure (Days) = min (Last date of exposure, death) – Date of first dose 
       Last date of exposure = Initial dose date of the last cycle + 21 – 1   
       Duration of Treatment (Days) = Date of last dose – Date of first dose + 1  
       Number of Cycles received (Cycles) = Number of cycles with at least one study drug 
       Total Dose Received during a Cycle= Sum of Doses received during that cycle 
       Cumulative Dose = Sum of (Total Dose Administreated during a Cycle)  
 
Number of patients with dose reductions, dose interruptions will be summarized by counts and 
percentages.   
 
3.11. 
Efficacy Analyses 
3.11.1. 
General Considerations 
All statistical analyses will be performed at the 5% significance level. All confidence intervals 
will be 2-sided 95% confidence intervals. Efficacy analyses will be carried out using the Efficacy 
Evaluable Population. Response to treatment will be evaluated using RECIST v1.1.  
Summary statistics (n, mean, standard deviation, median, minimum and maximum for 
continuous variables, and number [%] of patients in each category for categorical variables) will 
be provided for all variables. Time-to-event variables will be summarized by Kaplan-Meier 
plots, medians, and ranges. Data from all study centers will be combined for analysis. No 
adjustments for multiple comparisons will be applied.  


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3.11.2. 
Efficacy Analysis for the Primary Efficacy Endpoint 
The primary efficacy endpoint is the rate of new or improved antitumor response (hereafter 
referred to as objective improvement) after the addition of ALKS 4230 treatment in patients 
receiving ongoing anti-PD-1 therapy but who have not achieved a CR.  
An objective improvement for patients within Group 1 (Cohorts 1 and 2) is defined as:  
• SD at screening that improves to PR or CR, 
• PR at screening that improves to CR  
 
An objective improvement for patients within Group 2 (Cohorts 3 and 4) is defined as:  
• PD at screening that improves to PR or CR  
 
Primary efficacy analysis will be evaluated in patients in the Efficacy Evaluable population for 
each group separately and overall. The objective improvement rate after continued anti-PD-1 
therapy with ALKS 4230 will be summarized by group (Group 1 and Group 2) separately and 
overall with descriptive statistics.  
Objective improvement rate for Group 1 =  
number of patients who achieved CR or PR
number of patients in Group 1
 
 
Objective improvement rate for Group 2 =  
number of patients who achieved CR or PR
number of patients in Group 2
 
The analysis of objective improvement rate using an exact binomial test will be conducted 
separately for each group. The two-sided 95% confidence interval (CI) on objective 
improvement rate will be estimated by Clopper-Pearson method. 
3.11.3. 
Efficacy Analysis for the Secondary Efficacy Endpoints 
 Secondary efficacy endpoints in this study include:  
• 
DOR, PFS, TTP, rate of non-progression at 6 months, and OS  
• 
Antitumor response rate of subsets of patients based on disease status (PR, SD, or 
PD) at screening  
• 
Antitumor activity as measured by radiological assessment compared to screening 
The efficacy analysis for the secondary endpoints will be performed for the following endpoints.  
• Duration of Response: 
Duration of response (DOR) is defined as the time from the first documentation of response 
CR or PR (whichever is first recorded) to the first documentation of objective tumor 
progression or death due to any cause. Patients who are alive and progression free on the 
analysis cut-off date will be censored at their last evaluable tumor response assessment 
before initiation of any new anticancer treatment. 
Patients with 2 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 
patient was documented to be progression free. The detailed censoring rules for DOR is in 
section 6.2.3. 


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DOR will be calculated as follows (in weeks):  
(date of disease progression/death – date of first response (CR or PR) + 1)/7 
The distribution of DOR will be estimated using Kaplan-Meier methodology. The median 
point estimate DOR will be provided along with the two-sided 95% CIs based on the 
Efficacy Evaluable population. Kaplan-Meier curves will be provided. 
• Progression-Free Survival: 
Progression-free survival (PFS) is defined as the time from the first dose to the first 
documentation of objective tumor progression, start of alternate therapy or death due to any 
cause. Patients who do not have disease progression or have not died will be censored at the 
last known time that the patient was progression free. If a patient begins a new anticancer 
treatment (either systemic or local) prior to documented progression or death, or if a patient 
is removed from the study due to undocumented clinical disease progression, then the patient 
will be censored at the last assessment where the patient was documented as progression free 
prior to the intervention. Patients with 2 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 patient was documented to be progression free. The detailed 
censoring rules for PFS is in section 6.2.2. 
Progression-free survival will be calculated as follows (in weeks): 
(date of disease progression/death – first dose date + 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 Efficacy 
Evaluable population. In addition, Kaplan-Meier curves will be provided. The 6-month PFS 
rate will be estimated using the Kaplan-Meier estimate. 
• Time to Progression: 
Time to progression (TTP) is defined as the time from the first dose to the confirmed tumor 
progression. All events of disease progression will be included regardless of whether the 
patient discontinued the study drug. If the patient has not experienced disease progression, 
the patient’s data will be censored at the date of last disease assessment. Data for patients 
without any disease assessments performed after the first dose will be censored at the date of 
first study drug. 
The TTP will be calculated as follows (in weeks):  
(date of disease progression – date of first dose + 1)/7 
TTP will be analyzed by Kaplan-Meier methodology. Median TTP will be calculated and 
95% confidence interval for median TTP will be presented.  
• Overall Survival: 
Overall survival (OS) is defined as the time from the first dose to death due to any cause. For 
patients without documentation of death, patients will be censored at the date that the patient 
was last known to be alive or the date of study cutoff, whichever comes earlier. The detailed 
censoring rules for OS is in section 6.2.1. 


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OS will be calculated as follows (in weeks): 
(date of death/censoring – date of first dose date + 1)/7 
OS will be analyzed by Kaplan-Meier methodology. Median OS will be calculated and 95% 
confidence interval for median OS will be presented. In addition, Kaplan-Meier curves will 
be provided. The one-year OS rate will be estimated using the Kaplan-Meier estimate. 
In addition, the objective response rate will be summarized for each of the 4 cohorts, and the 
percentage change from baseline in target lesions will be summarized by group and overall.  
3.13. 
Safety Analysis 
3.13.1. 
General Considerations 
All safety endpoints will be summarized for the Safety Population. 
3.13.2. 
Adverse Events  
Analyses of AEs will include only "treatment-emergent" AEs (TEAEs). TEAEs are defined as 
any AE that begins on or after the first administration of the study drug. Events where the onset 
date was the same as the study drug start date will be assumed to be treatment-emergent, unless 
the study drug start time and the AE start time are collected, and the AE start time is prior to the 
study drug start time. If an incomplete onset date is collected for an AE, the AE will be assumed 
to be treatment-emergent unless there is evidence that confirms that the AE was not treatment-
emergent (eg, the AE end date is prior to the date of the first dose of study drug). No imputation 
will be performed for partial dates for AE. Analyses will not include those that have an onset 
greater than 30 days after study drug discontinuation. 
Treatment-related AEs reported beyond 30 days after study drug discontinuation will be 
summarized separately during post treatment discontinuation period. 
TEAEs will be summarized by Preferred Term (PT) within a System Organ Class (SOC) 
according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 or higher.   
Patients reporting more than one AE within a SOC will be counted only once for that SOC. 
Patients reporting the same AE more than once will be counted only once for that PT. For 
summaries of TEAEs by the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE 5.0) grade, at each level of summation each patient is counted 


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only once at the maximum grade level. The possible grade levels are 1 to 5, and unknown. If a 
patient had an AE with unknown grade, then the patient will be counted in the grade category of 
"unknown," even if the patient had another occurrence of the same event with a grade of 1 or 2. 
If the patient had another occurrence of the same AE with a grade of 3, 4 or 5, the patient will be 
counted under the grade 3, 4 or 5 categories based on the maximum grade level reported. 
The number and percentage of patients experiencing at least one TEAE will be further 
summarized as follows.  
• Any TEAE 
• Any TEAE experienced by ≥10% of patients 
• Any TEAE with NCI CTCAE toxicity ≥ Grade 3  
• Any TEAE broken down by maximum NCI CTCAE toxicity grade (severity) 
• Any TEAE related to ALKS 4230 as assessed by the Investigator 
• Any TEAE related to pembrolizumab as assessed by the Investigator 
• Any TEAE with NCI CTCAE toxicity ≥Grade 3 and related to ALKS 4230 as assessed 
by the Investigator 
• Any TEAE with NCI CTCAE toxicity ≥Grade 3 and related to pembrolizumab as 
assessed by the Investigator 
• Any Treatment Emergent Serious Adverse Event (SAE) 
• Any SAE related to ALKS 4230 as assessed by the Investigator 
• Any SAE related to pembrolizumab as assessed by the Investigator 
• Any SAE related to ALKS 4230 with NCI CTCAE > Grade 3 as assessed by the 
Investigator 
• Any SAE related to pembrolizumab with NCI CTCAE > Grade 3 as assessed by the 
Investigator 
• Any TEAE leading to discontinuation of ALKS 4230 
• Any TEAE leading to dose interruption of ALKS 4230 
• Any TEAE leading to dose reduction of ALKS 4230 
• Any TEAE leading to discontinuation of pembrolizumab 
• Any TEAE leading to death 
The tables will be sorted by overall descending frequency of SOC and then, within a SOC, by 
overall descending frequency of PT based on the patient count for the overall column.  
The original date and time will be shown on all listings of AEs. Listings will be provided for all 
TEAEs, serious TEAEs, and TEAEs leading to study treatment discontinuation.The data listings 
will be provided for dose reductions, and dose interruptions along with the AE/SAE that was 
associated with the change in dosing for ALKS 4230 and pembrolizumab separately. 
3.13.3. 
Death 
Listings will be provided for patients who died during the study for any reason, and for patients 
who had died due to AE.  


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3.13.4. 
Clinical Laboratory Parameters 
Laboratory parameters will be presented in conventional (ie, US) units. Only scheduled laboratory 
parameters, as specified in Table 1, will be included in the laboratory results summaries, unless 
specified otherwise. All laboratory data, including those collected at unscheduled visits, will be 
included in the listings.  
For all quantitative parameters listed in Table 1, the actual value and the change from baseline to 
each postbaseline visit will be summarized by visit using descriptive statistics.  Only data 
collected as scheduled will be included in the summaries. For each parameter, the mean (+/- SE) 
at each scheduled visit will be plotted for its actual value and its change from baseline. Data 
collected at the EOS/ET visit will be included as one time point regardless of subjects’ EOS 
status. 
In addition, where applicable, hematology and chemistry laboratory determinations will be 
categorized according to NCI CTCAE (version 5) grades and shifts from baseline NCI CTCAE 
grades to maximum and final post-baseline grades will be assessed. The baseline and final grades 
will be defined respectively as the grade of the last measurement collected prior to the first dose 
of study drug, and as the last post-baseline measurement collected no more than 30 days after the 
last dose of study drug.  
The maximum NCI CTCAE toxicity grade value will be the value with the highest NCI CTCAE 
toxicity grade collected after the first dose of study drug and within 30 days following study drug 
discontinuation. In cases where multiple values are collected on the same day, the maximum grade 
value will be selected as the value for that day. 
The number and percentage of patients with baseline grades versus maximum post-baseline 
grades of and baseline grades versus final post-baseline grades will be summarized. 
Detailed listings of data for subjects experiencing NCI CTCAE grade ≥3 hematology and 
chemistry values will be provided. All measurements collected, regardless of the number of days 
after study drug discontinuation will be included in these listings.  
Pregnancy test data will be listed. 
Number of subjects who meet protocol defined event of clinical interest criteria (Section 12.1.1 
of protocol) as below will be summarized and corresponding listing will be presented. 
• An elevated aspartate aminotransferase or alanine aminotransferase 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.  
For urinalysis, the number of abnormalities at any post-baseline visit will be summarized. 


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Table 1: 
Clinical Laboratory Assessments 
Hematology 
Chemistry 
Urinalysis 
Other 
• Haematocrit  
• Haemoglobin  
• Red blood cell 
count (RBC) 
• Total white blood 
cell count (WBC)  
• Platelet count  
• Differential blood 
count including:  
o Basophils  
o Eosinophils 
o Neutrophils 
o Lymphocyte
s 
o Monocyte 
 
• 
Sodium  
• 
Potassium  
• 
Phosphorus  
• 
Glucose  
• 
Total protein  
• 
BUN  
• 
Serum creatinine  
• 
CrCl  
• 
Albumin  
• 
Total bilirubin  
• 
ALT  
• 
AST  
• 
LDH  
• 
ALK-P  
• 
CO2 or 
bicarbonatea 
• 
Uric acid  
• 
Calcium  
• 
Chloride  
• 
Magnesium  
• Direct bilirubin, 
if total bilirubin 
is elevated above 
the upper limit of 
normal  
 
• 
Specific gravity  
• 
Protein  
• 
pH  
• 
Glucose  
• 
Ketones  
• 
Blood  
• 
Microscopic 
examination of 
sediment, only if 
urinalysis 
dipstick results 
are abnormal 
(2+ or higher)  
• 
Urine pregnancy 
testb  
• 
Serum β-hCGb 
• 
PT (INR) 
• 
aPTT  
• 
TSH  
• 
Cortisol 
(morning)  
• 
ACTH 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ALK-P=alkaline phosphatase; ALT=alanine aminotransferase; 
ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; CBC=complete blood count; CO2=carbon dioxide; CrCl=creatinine clearance; 
hCG=human chorionic gonadotropin; INR=international normalized ratio; LDH=lactic dehydrogenase; 
PT=prothrombin time; TSH=thyroid-stimulating hormone.  
a If considered standard of care in local region.  
b Perform on women of childbearing potential 
3.13.5. 
Vital Signs 
Vital signs assessments include respiratory rate, temperature, blood pressure, and heart rate. The 
observed values at each visit and change from baseline to post-baseline visits will be summarized 
with descriptive statistics. All vital sign data will be presented in the patient data listings.  


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 Patients who meet PCS criteria will be summarized for vital signs parameters. 
The figure of mean (+/- SE) of the change from baseline will be summarized by visit for systolic 
blood pressure, diastolic blood pressure, heart rate and temperature. 
3.13.6. 
Electrocardiograms (ECG) 
ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT interval will be 
summarized for each visit during the study. QT interval changes from baseline will also be 
descriptively summarized for each visit. The baseline value will be taken as the average of the 
triplicate ECG measurements taken prior to the first dose on Cycle 1 Day 1.  
The number and percent of patients with abnormal ECG findings at any postbaseline visit will be 
summarized. 
Individual ECG evaluation results will be provided in data listings. A supportive listing will 
present all values for a parameter for patients with abnormal ECG results. 
3.13.7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG Performance Status assesses the patients’ activity status. Descriptions of activity status 
are presented in Table 2. Possible scores are 0 to 5. The number and percentage of patients with 
baseline score versus post-baseline scores will be summarized in a shift table. The data will be 
presented in the patient data listings. 
Table 2: 
Eastern Cooperative Oncology Group Performance Status 
Grade Description 
0  
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work).  
2  
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours.  
3  
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.  
4  
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.  
5  
Dead  


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4. 
INTERIM ANALYSES  
No interim analyses are planned for this study. 


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5. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM 
THE PROTOCOL 
There are no changes made to the statistical methods specified in the ION-01-ALKS 4230 study 
protocol (dated 29 Dec 2018). 
5.1. 
Revisions and/or clarification of definitions in SAP  
 
Protocol Definition  
SAP definition  
Efficay Evaluable Population  
All patients who received at least 1 dose of 
both study drugs 
Efficacy Evaluable Population 
All patients who received at least 1 dose of 
both study drugs and have minimum of one 
post-baseline scan 
 


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6. 
DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE 
DATA 
Dataset specifications will be provided in a separate document. 
6.1. 
Analysis Visit Windows 
Scheduled analysis visits are visits at scheduled timepoints as specified in the protocol (Table 1 
Schedule of Assessments and Study Visits). 
Scheduled analysis visits during the study period will be the same as the nominal visits collected 
in the eCRF. There will be one valid value of assessment kept for each scheduled analysis visit in 
summary/analysis statistics.  
In the event that a patient chooses to withdraw from the study, the Investigator should make a 
reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the patient’s 
rights. Enrolled patients are to be asked to return to the clinic for an End of Treatment (EOT) 
Visit. The EOT Visit should be scheduled as close as possible to the patient’s last dose, and early 
termination assessments will follow the assessments scheduled to be conducted at the EOT Visit. 
Unscheduled visits are visits with data collected outside of scheduled time points. Unscheduled 
visits will not be used for by-visit summary/analysis statistics, unless specified otherwise. 
All unscheduled visits as collected in the eCRF will be included in listings. 
Visit Day is calculated as (date of visit) – (date of the first dose of study drug) +1 day. 
 
6.2. 
Efficacy Data Handling 
The Censoring Rules for Overall Survival, Progression Free Survival and Duration of Response 
are defined according to the FDA guidance2.  
 
6.2.1   
Censoring Rules for Overall Survival (OS) 
The overall survival censoring date for a patient is listed in Table 3. The start date is the first 
dose date of the study drug. 
Table 3: 
Censoring Rules for Overall Survival (OS) 
Situation 
Date of Death or 
Censoring 
Outcome  
Death during study 
Date of death 
Death 
Patient still alive at data 
cut-off/death occurred 
after data cut-off 
Date of cut-off 
Censored 
Patient lost to follow-up 
before data cut-off 
Date last known to be 
alive 
Censored 
 
 


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6.2.1. 
Censoring Rules for Duration of Response (DOR) 
The Duration of Response censoring dates for a patient is in Table 4. The Start date: the date of 
first documentation of response (CR or PR). 
Table 4: 
Censoring Rules for Duration of Response 
Situation 
Date of Progression or Censoring 
Outcome  
No baseline or unreadable baseline 
assessment, but readable post-baseline 
assessments 
Date of the 1st dose of the study drug 
Censored 
Progression documented between 
scheduled visits 
Earliest of 
• 
Date of radiological assessment showing 
new lesion (if progression is based on new 
lesion); or 
• 
Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions) 
Progressed  
Death before first PD assessment 
Date of death 
Progressed  
Death between adequate assessment visits Date of death 
Progressed 
Treatment discontinuation for 
undocumented progression 
Date of last tumor assessment with no documented 
progression 
Censored 
Treatment discontinuation for toxicity of 
other reason  
Date of last tumor assessment with no documented 
progression 
Censored 
Patients still on treatment without PD as of 
data cut-off 
Date of last tumor assessment  
Censored 
Treatment discontinuation for other than 
PD or death with post-baseline tumor 
assessments  
Date of last tumor assessment  
Censored 
New anticancer treatment started before PD 
or death 
Date of last tumor assessment before start of new 
treatment 
Censored 
Death or PD after two or more missed 
tumor assessments 
Date of the last tumor assessment before missed 
assessments 
Censored 
Only NE assessments after CR, PR, SD 
Date of last tumor assessment before NE assessments Censored 


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6.2.2. 
Censoring Rules for Progression Free Survival (PFS)  
The Progression Free Survival censoring dates for a patient is listed in Table 5. The start date is 
the first dose date of the study drug. 
Table 5: 
Censoring Rules for Progression Free Survival 
Situation 
Date of Progression or Censoring 
Outcome  
No baseline or unreadable baseline 
assessment, but readable post-baseline 
assessments 
Date of the 1st dose of the study drug 
Censored 
Progression documented between 
scheduled visits 
Earliest of 
• 
Date of radiological assessment showing 
new lesion (if progression is based on new 
lesion); or 
• 
Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions) 
Progressed  
Death before first PD assessment 
Date of death 
Progressed  
Death between adequate assessment visits Date of death 
Progressed 
Treatment discontinuation for 
undocumented progression 
Date of last tumor assessment with no documented 
progression 
Censored 
Treatment discontinuation for toxicity of 
other reason  
Date of last tumor assessment with no documented 
progression 
Censored 
Patients still on treatment without PD as of 
data cut-off 
Date of last tumor assessment  
Censored 
Treatment discontinuation for other than 
PD or death with post-baseline tumor 
assessments  
Date of last tumor assessment  
Censored 
New anticancer treatment started before PD 
or death 
Date of last tumor assessment before start of new 
treatment 
Censored 
Death or PD after two or more missed 
tumor assessments 
Date of the last tumor assessment before missed 
assessments 
Censored 
Only NE assessments after CR, PR, SD 
Date of last tumor assessment before NE assessments Censored 


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6.3. 
Safety Data Handling 
All effort should be made to obtain missing information from the Investigator. For vital signs, 
laboratory testing (chemistry, hematology, urinalysis), and 12-lead ECGs, only observed data 
will be used for analyses, and missing data will not be imputed. 
6.4. 
Handling of Partial Dates of Concomitant Medication 
Partial start dates of prior and concomitant medication will be assumed to be the earliest possible 
date consistent with the partial date. Partial stop dates of prior and concomitant medications will 
be assumed to be the latest possible date consistent with the partial date. In the case of 
completely missing stop date, medication will be assumed to be ongoing. 
For summaries of prior medications, if an incomplete start date is collected for a medication, the 
medication will be assumed to be a concomitant medication unless there is evidence that 
confirms that the medication was not a concomitant medication (eg, the medication end date is 
prior to the first dose of study drug) 
If both the start and end date of medication are missing, then these will be excluded from 
summary statistics but included in the patient data listings. 
 


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7. 
GENERAL STATISTICAL METHODOLOGY 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of patients in each category for categorical variables) will 
be provided. All summary tables will be based on observed data, and missing values will not be 
imputed unless otherwise indicated. Measurements collected from unscheduled visits or repeated 
assessments will not be included in the by-visit summary tables or figures but will be included in 
the derivation of the last post-baseline value during treatment, the analyses for the PCS post-
baseline values, and patient listings. Source data for the summary tables and statistical analyses 
will be presented as patient data listings. 
7.1. 
Reporting Precision 
Summary statistics will be presented to the degree of precision in Table 6, unless otherwise 
specified: 
Table 6: 
Degree of Precision 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places 
Minimum, Maximum 
The same as the raw data, up to 2 decimal places 
p-value 
Rounded to 3 decimal places and therefore presented 
as 0.xxx; p-values smaller than 0.001 as ‘<0.001’; p-
values greater than 0.999 as ‘>0.999’. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12–0.30). 
For weight, height, and body mass index (BMI), one decimal place will be used for summary 
statistics. 


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8. 
PROGRAMMING SPECIFICATIONS 
Programming specifications will be provided in a separate document. 


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9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
Mock-up tables and listings will be provided in a separate document. 
 


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10. 
REFERENCES 
1 Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic 
head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-
012. Br J Cancer. 2018;119(2):153-159. doi: 10.1038/s41416-018-0131-9. 
2 Clinical Trial Endpoints for Approval of Non-Small Cell Lung Cancer Drugs and Biologics 
Guidance for Industry. April 2015; 14-16.