Clinical trial NCT03331341
Conditions: Classical Hodgkin Lymphoma
Keywords: Hodgkin Lymphoma
Sponsor: University of Washington
Start date: 2019-01-09; Completion date: 2023-12-21
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects of doxorubicin hydrochloride, pembrolizumab, vinblastine, and dacarbazine in treating patients with classical Hodgkin lymphoma. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine, and dacarbazine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with pembrolizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride, pembrolizumab, vinblastine, and dacarbazine may work better in treating classical Hodgkin lymphoma.

Detailed description:
OUTLINE:

PART A: Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine IV, and dacarbazine IV on days 1 and 15. Patients also receive pembrolizumab IV over 30 minutes on days 1 and 22 of cycle 1 and on day 15 of cycle 2. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive doxorubicin hydrochloride IV, vinblastine IV, dacarbazine IV, and pembrolizumab IV as in part A, but undergo a total of 6 treatment cycles.

After completion of study treatment, patients are followed up at 30 days and then up to 5 years.

Arms: arm 1: PART A: Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine IV, and dacarbazine IV on days 1 and 15. Patients also receive pembrolizumab IV over 30 minutes on days 1 and 22 of cycle 1 and on day 15 of cycle 2. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive doxorubicin hydrochloride IV, vinblastine IV, dacarbazine IV, and pembrolizumab IV as in part A, but undergo a total of 6 treatment cycles.
Interventions: intervention 1: Dacarbazine intervention 2: Doxorubicin Hydrochloride intervention 3: Laboratory Biomarker Analysis intervention 4: Pembrolizumab intervention 5: Vinblastine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Protocol v7.0 dated 16Dec2022  
1 of 61
CC9805
A Pilot Trial of Adriamycin, Pembrolizumab, Vinblastine and Dacarbazine (APVD) for patients 
with Untreated Classical Hodgkin Lymphoma
Current Protocol: Version 7.0 dated 16Dec2022 
Previous Protocol: Version 6.1 dated 26 Aug 2021
INVESTIGATOR: 
 
Ryan C. Lynch, MD
Assistant Professor, UWMC
Fred Hutchinson Cancer Center825 Eastlake Ave. E LG-650
Seattle, WA  98109
Telephone: (206) 606-1739
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
2 of 61
Contents
1.0
TRIAL SUMMARY ....................................................................................................5
2.0
TRIAL DESIGN ..........................................................................................................5
2.1
Trial Design ......................................................................................................................................5
2.2
Trial Diagram ...................................................................................................................................6
3.0
OBJECTIVES & Hypotheses ...................................................................................10
3.1
Primary Objectives & Hypotheses .................................................................................................10
3.2
Secondary Objective & Hypotheses...............................................................................................10
3.3
Exploratory Objective....................................................................................................................10
3.4
Background....................................................................................................................................10
3.4.1
Pharmaceutical and Therapeutic Background....................................................................12
3.4.2
Preclinical and Clinical Trial Data........................................................................................13
3.5
Rationale........................................................................................................................................13
3.5.1
Rationale for the Trial and Selected Population.................................................................13
3.5.2
Dosing Justification for Dose ..............................................................................................13
3.5.3
Rationale for Endpoints ......................................................................................................14
3.5.4
Efficacy Endpoints...............................................................................................................15
3.5.5
Biomarker Research............................................................................................................15
4.0
Methodology...............................................................................................................15
4.1 
Study Population ........................................................................................................................15
4.1.1
Eligibility Criteria.................................................................................................................15
4.1.2
Lifestyle Restrictions...........................................................................................................17
4.1.3
Pregnancy ...........................................................................................................................17
4.1.4
Use in Nursing Women.......................................................................................................18
4.2
Trial Treatments ............................................................................................................................18
4.2.1 Timing of Dose Administration ..................................................................................................18
4.2.2
Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab...................................................................................................................................19
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
3 of 61
4.3
Stratification ..................................................................................................................................27

The Ann Arbor staging criteria will be utilized;...........................................................................27

The GHLSG Risk Stratification will be used for all patients with early stage disease..................27

The Hasenclever score will be used for all patients with advanced disease. .............................27

Bulk will be defined as the long axis of the single largest nodal mass........................................27
4.3.1
Acceptable Concomitant Medications................................................................................27
4.3.2
Prohibited Concomitant Medications.................................................................................27
4.3.3
Rescue Medications & Supportive Care..............................................................................28
4.4
Participant Withdrawal/Discontinuation Criteria..........................................................................28
4.5
Participant Replacement Strategy.................................................................................................29
4.6
Clinical Criteria for Early Trial Termination....................................................................................29
5.0
STUDY FLOW CHART ...........................................................................................30
6.0
TRIAL PROCEDURES ............................................................................................31
6.1
Trial Procedures.............................................................................................................................31
6.1.2
Clinical Procedures/Assessments .......................................................................................33
6.1.3
Laboratory Procedures/Assessments .................................................................................34
6.1.4
Other Procedures................................................................................................................36
6.2
Assessing and Recording Adverse Events......................................................................................37
6.2.1
Expedited Reporting ...........................................................................................................37
6.3
Overdose and Reporting Requirements ........................................................................................37
6.3.1
Reporting of Pregnancy and Lactation to the Sponsor and to Merck.................................37
6.3.1.1.1 Evaluating Adverse Events...................................................................................................39
6.3.2
Sponsor Responsibility for Reporting Adverse Events........................................................44
7.0
STATISTICAL ANALYSIS PLAN .........................................................................45
7.1
Statistical Analysis Plan..................................................................................................................45
8.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................47
8.1
Investigational Product..................................................................................................................47
8.2
Packaging and Labeling Information .............................................................................................47
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
4 of 61
8.3
Clinical Supplies Disclosure............................................................................................................47
8.4
Storage and Handling Requirements.............................................................................................47
8.5
Returns and Reconciliation............................................................................................................47
9.0
DATA AND SAFETY MONITORING PLAN .......................................................48
9.1
RECORDS........................................................................................................................................48
9.2
REGULATORY RESPONSIBILITIES OF SPONSOR-INVESTIGATOR.....................................................49
10.0   References.....................................................................................................................49
11.0
APPENDICES............................................................................................................53
Appendix 1: ECOG Performance Status..................................................................................................53
Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ......................................54
Appendix 4: Contraceptive Guidance and Pregnancy Testing................................................................60
Contraception Requirements ..............................................................................................................60
Pregnancy Testing ..............................................................................................................................62
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
5 of 61
1.0 TRIAL SUMMARY
Abbreviated Title
Adriamycin, Pembrolizumab, Vinblastine and Dacarbazine (APVD) in 
Untreated cHL
Trial Phase
Pilot
Clinical Indication
Untreated Classical Hodgkin Lymphoma
Trial Type
Nonrandomized, single arm prospective clinical trial
Type of control
N/A
Route of administration
IV
Trial Blinding
N/A
Treatment Groups 
Untreated Classical Hodgkin Lymphoma
Number of trial participants
Part A: 30
Part B: 20
Estimated enrollment period
36 months
Estimated duration of trial
48 months
Duration of Participation
48 months
Estimated average length of 
treatment per patient
2 months
2.0 TRIAL DESIGN
2.1
Trial Design
This is a nonrandomized, single-arm pilot study designed to evaluate Adriamycin, 
Pembrolizumab, Vinblastine, and Dacarbazine for 2 cycles (28 day cycle length) in patients 
with untreated Classical Hodgkin Lymphoma.  Patients can receive an additional 4 cycles, 
up to a total of 6 cycles of APVD at the discretion of the treating provider (Part A only). All 
subjects should receive 6 total cycles in Part B.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
6 of 61
2.2
Trial Diagram
Part A
Registration (any stage untreated Hodgkin lymphoma)
Adriamycin, Vinblastine and Dacarbazine given on days 1 and 15 for 2 cycles (28 day cycle length). 
Pembrolizumab given on cycle 1 day 1, cycle 1 day 22, and cycle 2 day 15.
Dosing Schema (Cycles 1-2) (Part A and Part B)
Cycle 1
Cycle 2
Day 
1
Day 
15
Day 
22
Day 
1
Day 
15
Doxorubicin 
25mg/m2
X
X
X
X
Pembrolizumab 
200 mg (fixed 
dose)
X
X
X
Vinblastine 6 
mg/m2
X
X
X
X
Dacarbazine 
(DTIC) 375 
mg/m2
X
X
X
X
Continuing treatment after the initial 2 cycles will be at the discretion of the treating physician up to a 
maximum of 6 cycles (Part A). The primary endpoint of this trial is to evaluate the safety of 2 cycles of 
APVD (Part A). 
Optional dosing schema for treatment cycle 3-6
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Day 1
Day 8
Day 
15
Day 1
Day 
15
Day 
22
Day 1
Day 
15
Day 1
Day 8
Day 
15
Doxorubicin 
25mg/m2
X
X
X
X
X
X
X
X
Pembrolizumab 
200 mg (fixed dose)
X
X
X
X
X
Vinblastine 6 
mg/m2
X
X
X
X
X
X
X
X
Dacarbazine 
(DTIC) 375 mg/m2
X
X
X
X
X
X
X
X
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
7 of 61
Part B
Registration (Stage III or IV untreated Hodgkin lymphoma)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Day 
1
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
Day 
8
Day 
15
Doxorubicin 25mg/m2
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab 
200 mg (fixed dose)
X
X
X
X
X
X
X
X
Vinblastine 6 mg/m2
X
X
X
X
X
X
X
X
X
X
X
X
Dacarbazine (DTIC) 375 
mg/m2
X
X
X
X
X
X
X
X
X
X
X
X
Primary endpoint for Part B to estimate the 1-year event free survival (EFS) for advanced stage patients treated with APVD. An event 
will be defined as progression, biopsy proven recurrence, initiation of next line of chemotherapy, or death.


Protocol v7.0 dated 16Dec2022  
8 of 61
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
9 of 61
3.0 OBJECTIVES & HYPOTHESES
3.1
Primary Objectives & Hypotheses
Objective: Part A: To estimate the safety of delivering 2 cycles APVD to patients with previously 
untreated cHL. Part B: To estimate the 1-year event free survival (EFS) for advanced stage patients 
treated with APVD. An event will be defined as progression, biopsy proven recurrence, initiation 
of next line of chemotherapy, or death.
Hypothesis: We hypothesize that a combination of pembrolizumab with AVD 
chemotherapy (Doxorubicin, Vinblastine and Dacarbazine) for use in the front line setting 
for chemotherapy naïve patients with cHL will be safe and potentially efficacious.
3.2
Secondary Objective & Hypotheses
Objective:  To estimate the FDG-PET2 negative (Deauville score 1-3) after 2 cycles of APVD.
3.3
Exploratory Objective
Objective: Overall survival, association of biomarkers with early CR. Predictive capacity of 
PET2 after APVD. To evaluate the impact of APVD on T-cell repertoire and diversity. To 
evaluate the ability of this regimen to attain minimal residual disease as measured by NGS. 
3.4
Background
Efficacy and limitations of ABVD
ABVD (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine) is a component of a standard 
regimen in North America for treatment of classical Hodgkin’s lymphoma (cHL) regardless of 
disease stage. It was originally developed in 1970, showed similar efficacy compared with MOPP 
regimen (Mechlorethamine, Vincristine, Procarbazine, and Prednisone) and more importantly had 
an improved tolerability and toxicity profile1. In the advanced cHL setting, ABVD use offers up 
to 70% long term tumor control rate2. However, up to 25% of patients do not respond completely 
to ABVD3. Additionally, of the initial responders relapse occurs in a significant proportion of 
patients who then require salvage chemotherapy, high dose chemotherapy, autologous stem cell 
transplant, brentuximab-vedotin, nivolumab or pembrolizumab4. Nevertheless, ABVD is still 
considered a standard frontline regimen for classical cHL despite the fact that up to one-third of 
patients will not be cured with this approach.
Toxicity of Bleomycin
ABVD use is associated with toxicities, both acute and long term. Bleomycin is most commonly 
implicated for causing severe toxicity, specifically, acute pulmonary toxicity - dyspnea on 
exertion, cough with dyspnea and decline in pulmonary function tests 5,6. These can be potentiated 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
10 of 61
with concomitant use of G-CSF, hence the limited use of growth factor to abrogate the frequent 
neutropenia induced with this regimen. Bleomycin can also induce long-term pulmonary toxicity. 
Elderly patients and those receiving radiation therapy are at a higher risk of this toxicity including 
mortality and for this reason it is typically omitted from ABVD when treating older patients7. 
Recent data indicate that bleomycin may be safely discontinued in select early patients with early 
complete remissions to mitigate and prevent further damage8,9.. 
Efficacy and Safety of PD-1 inhibition in cHL. 
Besides cytotoxic chemotherapy, promising results have been seen with checkpoint blockade 
based cancer immunotherapy in cHL. Tumors evade the T cell anti-tumor activity by blocking the 
PD-1/PD-L1/PD-L2 pathway. In cHL overexpression of PD-1 ligands in the RS cells10 and the 
tumor associated macrophages11 is seen. These cells engage the PD-1 receptor on the T cells, thus 
inducing immune tolerance. This allows tumor to evade the immune surveillance10. 
Pembrolizumab is a humanized IgG4 anti-PD-1 antibodies which blocks T cell inhibition, thereby 
enhancing anti-tumor T cell activity12. Pembrolizumab and the anti-PD-1 are both FDA approved 
for treatment of relapsed/refractory cHL patients based on 4 studies13, though pembrolizumab has 
a broader label of approval. Pembrolizumab demonstrated a 65% overall response rate 
(KETNOTE 13) in the first trial at a dose of 10mg/kg every 2 weeks and an overall response rate 
of 69% in the KEYNOTE-87 trial at a dose of 200mg every 3 weeks 14, 15. The patients in these 
studies were heavily pre-treated with chemotherapy, autologous stem cell transplant and novel 
antibody drug conjugate, Brentuximab-Vedotin. Pembrolizumab was overall well tolerated, no 
grade 4-5 drug related toxicities were noted in ≥5% of the patients. 
Front Line Use and Combinations of anti-PD1 and chemotherapy:
Both Pembrolizumab and Nivolumab have been successfully used as part of intial therapy and 
combined with chemotherapy further improve the response rates 15, 16, 17, 18. It is postulated that 
chemotherapy causes release of tumor antigens and in this setting the immune response can be 
further potentiated by using checkpoint inhibition. In a phase I study the safety and efficacy of 
Nivolumab combined with platinum based doublet chemotherapy for first line treatment of 
advanced NSLC was reported. Among the 95 patients treated in this study, no dose limiting 
occurred in the first 6 weeks of therapy. 45% patients reported grade 3 or 4 treatment related 
adverse effects. The safety profile was felt to be consistent with that expected for the agents.19  
Similar results have been observed using pembrolizumab as part of initial therapy 20-22. For 
example, the large KEYNOTE-21 showed no higher rates of AEs ≥ grade 3 in the chemo alone or 
chemo+pembrolizumab groups22.  In further support of this approach in patients with lymphoma 
we are currently carrying out a phase II trial of pembrolizumab + R-CHOP in patients with 
untreated DLBCL with no apparent increase in toxicity over R-CHOP alone (Smith et al- 
unpublished data). 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, 
thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
11 of 61
programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an intravenous (IV) immunotherapy for advanced malignancies.  Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications 
because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure.
3.4.1 Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades1.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma [Dudley et al., 2005; Hunder et al., 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald et al., 2005; Okazaki et al., 2001].
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-
1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved 
in the CD3 T-cell signaling cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et 
al., 2004; and Riley, 2009].  The mechanism by which PD-1 down-modulates T-cell responses 
is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins [Parry et al., 2005; Francisco, 2010].  As a consequence, 
the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in [disease under 
study]. 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
12 of 61
3.4.2 Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for Preclinical and Clinical data.
3.5
Rationale
3.5.1 Rationale for the Trial and Selected Population
The selected patient population is patients with untreated Classical Hodgkin Lymphoma.  
Pembrolizumab can be safely combined with a variety of chemotherapeutic agents in the front 
line setting, has a >60% response rate as a single agent in patients with highly-refractory cHL 
and a toxicity profile that is non-overlapping with AVD chemotherapy. Though not compared in 
a head-to head fashion, the clinical activity of pembrolizumab appears superior to what one 
would expect with single agent bleomycin and potentially brentuximab-vedotin. Recent data also 
suggest that omitting bleomycin in responding patients is safe and retains efficacy and is a 
standard of care in select patients. We hypothesize that the proposed APVD regimen may offer 
better efficacy and better tolerability in the front line setting for treatment of classical cHL. This 
study will address the safety of a minimum of 2 cycles of APVD as a first step toward 
incorporating PD1 blockade as part of front line therapy.
Early activity of APVD
Accrual on this study began in February 2020, and as of May 21, 2021, 29 of the original 
30 planned patients have been enrolled (unpublished data). We noted a CR rate of 65% 
on interim PET (slightly lower than previously presented in standard ABVD2). 5 patients 
so far have had a positive PET at end of treatment, but only one patient so far has had 
evidence of progressive CHL. 80% (4/5) of patients with FDG uptake post treatment 
never progressed at 8, 9, 18, and 19 months. These patients were either followed with 
serial imaging with resolution or underwent a biopsy.
These findings raise concerns that traditional methods of PET response assessment may 
be prone to false positives in patients treated with checkpoint inhibitor combinations. For 
this reason, we will plan to treat an additional 20 advanced stage patients with this 
regimen in order to better assess the activity of this regimen using a 1-year EFS endpoint.
3.5.2 Dosing Justification for Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined below, 
this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
13 of 61

Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment naïve, 
previously treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 
Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W 
versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006).  All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided 
similar responses to the highest doses studied.  Subsequently, flat dose-exposure-response relationships 
were also observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in KN001 
evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of PD-1 in 
systemic circulation at doses much lower than 200 mg Q3W.  Second, a PBPK analysis was conducted to 
predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression.  This 
evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood 
and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight and 
other participant covariates on exposure, has shown that the fixed-dosing provides similar control of PK 
variability as weight based dosing, with considerable overlap in the distribution of exposures from the 
200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported by these PK characteristics, and given that 
fixed-dose has advantages of reduced dosing complexity and reduced potential of dosing errors, the 200 
mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols.
3.5.3
Rationale for Endpoints
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – response will be defined by 
standard NCI criteria (Lugano 2014) for lymphoid malignancies.
Primary endpoint (Part A): The primary objective of this study is to estimate the safety of 2 cycles of 
APVD. Historical data regarding the tolerability of 2 cycles of ABVD are limited. In a recent trial of 
AVD+ brentuximab vedotin, 4 of 26 (~15%) patients were reported to be unable to complete treatment. 
We will be more conservatively scoring treatment delay due to toxicity rather than inability to complete 
the entire treatment course. Thus, we will deem this regimen safe if >85% of patients are able to complete 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
14 of 61
2 cycles of APVD without a dose delay of >3 weeks. This will be employed as a stopping rule and serve 
as the primary endpoint.
Part B: We plan to estimate the efficacy of this regimen using advanced stage patients (who are at higher 
risk of recurrence) with a projection that 1-year EFS will be at least as good as the 85% demonstrated in 
the ECHELON-1 study between the two arms3. See statistical section for detail.
3.5.4
Efficacy Endpoints
Secondary and Exploratory endpoints will examine the efficacy of this regimen. Our secondary 
endpoint is to estimate the proportion of FDG-PET2 negative (Deauville score 1-3) patients after 2 
cycles of APVD. Exploratory endpoints will estimate overall and progression free survival.
3.5.5
Biomarker Research
Correlative studies may be conducted whenever possible and may include PD1/PLDL1/PDL2 
expression, MRD (e.g. Adaptive Clonoseq or similar) and cytokine monitoring.  Tissue-based 
assays for tumor and immune infiltrate may be conducted when archival tissue is available.  
4.0 METHODOLOGY 
4.1 
Study Population
4.1.1 Eligibility Criteria
4.1.1.1
Participant Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Patients must have cHL that has not been previously treated 
-
Part A: Any stage
-
Part B: Must be stage 3 or 4
2.
Patients must be appropriate candidates for at least 2 cycles of ABVD (6 
cycles for Part B patients) or AVD (this could include patients ranging from 
favorable risk early stage disease to poor prognosis advanced stage disease). 
3.
Patients must have measurable FDG-avid disease defined by standard 
criteria (Lugano 2014) and a minimum of 1.0 cm in diameter. 
4.
Patients should not have evidence of active central nervous system 
lymphoma.
5.
Patients must have an ECOG performance status of 0 or 1.
6.
Patients must be 18 years of age or older. 
7.
Patients must have a LVEF ≥50% within 56 days of enrollment.
9.
Patients must have adequate labs within 10 days of treatment.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
15 of 61
Bone Marrow Function: ANC   500/mm3, platelets  25,000/mm3 (without 
transfusion or growth factor support), hemoglobin  8 g/dL. Growth factor 
and/or transfusion support is permissible to stabilize participant prior to 
study treatment if needed. There is no lower limit to cytopenias if related to 
bone marrow involvement.
Renal Function: serum creatinine < 1.5 x ULN or creatinine clearance 
greater than 30/ml per minute by Cockcroft Gault formula 
Hepatic function: total bilirubin ≤ 1.5 times upper limit of normal OR direct 
bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN), 
AST and ALT ≤ 2.5 times upper limit of normal (≤5 × ULN for participants 
with liver metastases)
10.  
All patients must be informed of the investigational nature of this study 
and have given written consent in accordance with institutional and federal 
guidelines.
11.
Patients must be anticipated to complete all planned study therapy.
12.
Male subjects should agree to use an adequate method of barrier 
contraception starting with the first dose of study therapy through 120 
days after the last dose of study therapy.
13.
Female subject of childbearing potential should have a negative urine or 
serum pregnancy 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.  
14. 
Female subjects of childbearing potential should be willing to use 2 
methods of birth control or be surgically sterile or abstain from 
heterosexual activity for the course of the study through 120 days after the 
last dose of study medication.  Subjects of childbearing potential are those 
who have not been surgically sterilized or have not been free from menses 
for > 1 year.
4.1.1.2
Participant Exclusion Criteria: 
Participants are excluded from the study if any of the following criteria apply:
1. Patients known positive for HIV, or infectious hepatitis type B or C.
2. Pregnant or nursing women. Men or women of reproductive potential may not 
participate unless they have agreed to use an effective contraceptive method. 
3. Patients with other prior malignancies except for adequately treated basal cell 
carcinoma, squamous cell carcinoma of the skin, breast or cervical cancer in 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
16 of 61
situ, or other cancer from which the patient has been disease-free for 5 years or 
greater, unless approved by the protocol Chair or Co-Chair.
4. Patients who have other medical conditions that would contraindicate treatment 
with aggressive chemotherapy (including active infection, uncontrolled 
hypertension, congestive heart failure, unstable angina pectoris, or myocardial 
infarction within the past 6 months, uncontrolled arrhythmia, severe pulmonary 
disease or requirement of supplemental oxygen). 
5. Active ischemic heart disease or congestive heart failure. 
6. Concurrent use of other anti-cancer agents or experimental treatments. 
7. Known current or prior autoimmune disease with the exception of vitiligo.
8. Active or prior history of pneumonitis/interstitial lung disease that required 
corticosteroids.
9. Current use of supplemental oxygen.
10. Is known to have received a live vaccine or live-attenuated vaccine within 30 
days prior to the first dose of trial treatment. Administration of killed vaccines 
is allowed.
4.1.2 Lifestyle Restrictions
4.1.2.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting.
4.1.2.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 4 for approved methods 
of contraception.
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).  
4.1.3 Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the participant 
will be immediately discontinued from study treatment.  The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to Merck within 2 working days if the outcome is a serious 
adverse experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study Investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn to 
Merck.  If a male participant impregnates his female partner, the study personnel at the site must be 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
17 of 61
informed immediately and the pregnancy must be reported to Merck and followed as described in Section 
6.3.1. 
4.1.4 Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment.
4.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table below.  Administration of APVD: Each 
cycle of therapy is given every 28 days with doses of doxorubicin, vinblastine, and dacarbazine on days 1 
and 15. Pembrolizumab will be given on cycle 1 day 1, cycle 1 day 22, and cycle 2 day 15. Two cycles 
should be given per protocol. Administration may be +/-2 days. Infusion details should be as per 
institutional standard of care. Dates for optional (mandatory for part B) cycles 3-6 are outlined in section 
2.2. Pembrolizumab will be administered first, followed by Doxorubicin, Vinblastine and Dacarbazine.
Drug 
Dose 
Route Days 
Doxorubicin 
25mg/m2 
IV 
1 and 15 
Vinblastine 
6mg/m2 
IV 
1 and 15 
Dacarbazine 
375 mg/m2 IV 
1 and 15 
Drug 
Dose 
Route Cycle/Days 
Pembrolizumab* 200mg 
IV 
Cycle 1 days 1 and 22, 
Cycle 2 day 15 (and 
cycles 3-6 at outlined in 
section 2.2)
Trial treatment should begin on the day of enrollment or as close as possible to the date on which 
treatment is allocated/assigned.
4.2.1 Timing of Dose Administration
Trial treatment of doxorubicin, vinblastine, and dacarbazine should be administered on Day 1 and 15 of 
each cycle after all procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 5.0).  Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks 
starting on cycle 1 day 1.  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 (i.e., infusion time is 30 minutes: -5 min/+10 min).
Each cycle of therapy is given every 28 days. Two cycles should be given per protocol. Administration 
may be +/-2 days. All other infusion details should be as per institutional standard of care. 
Pembrolizumab will be administered first, followed by Doxorubicin, Vinblastine and Dacarbazine.  
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
18 of 61
All trial treatments will be administered on an outpatient basis.
Growth factor support will be at the discretion of the treating team. Growth factors should be avoided 
whenever possible within 10 days of FDG-PET imaging. Antibiotic and antiemetic prophylaxis will be 
per institutional standard of care. 
4.2.2 Dose Modification and toxicity management for immune-related AEs 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 supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 3. 
Fred Hutch IRB
Approved 
10/18/2023


 Protocol v7.0 dated 16Dec2022  
19 of 61
Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics for 
opportunistic infections
  Monitor participants for signs and symptoms of 
pneumonitis
  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Diarrhea/Colitis 
Grade 2 or 3
Withhold
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 


 Protocol v7.0 dated 16Dec2022  
20 of 61
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
and of bowel perforation (ie, peritoneal signs 
and ileus)
  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Grade 2 a
Withhold
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes


 Protocol v7.0 dated 16Dec2022  
21 of 61
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
evidence of 
-cell failure
  Administer antihyperglycemic in 
participants with hyperglycemia
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function
Neurological 
Grade 2
Withhold
  Based on severity of AE administer 
  Ensure adequate evaluation to confirm etiology 


 Protocol v7.0 dated 16Dec2022  
22 of 61
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Toxicities
Grade 3 or 4
Permanently 
discontinue
corticosteroids
and/or exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Suspected SJS, 
TEN, or 
DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal


 Protocol v7.0 dated 16Dec2022  
23 of 61
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
Dose modification and toxicity management of infusion-reactions related to pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 4. 


 Protocol v7.0 dated 16Dec2022  
24 of 61
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
_____ with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
No subsequent dosing


 Protocol v7.0 dated 16Dec2022  
25 of 61
Table 4  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
Other allowed dose interruption for 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. Participants 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.
Life-threatening; pressor or 
ventilatory support indicated
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug 
treatment.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 


Protocol v7.0 dated 16Dec2022  
26 of 61
4.2.3  Randomization or Treatment Allocation
Patients will not be randomized and will receive APVD.
4.3
Stratification

The Ann Arbor staging criteria will be utilized; 

The GHLSG Risk Stratification will be used for all patients with early stage disease. 

The Hasenclever score will be used for all patients with advanced disease. 

Bulk will be defined as the long axis of the single largest nodal mass.
Concomitant Medications/Vaccinations (allowed & prohibited) Medications used during the course of 
the study should be documented.
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the participant’s primary physician. 
4.3.1 Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 6.1.2.1.
4.3.2 Prohibited Concomitant Medications
The administration of concurrent medications intended to treat the primary cancer is not allowed 
during protocol therapy.  This includes any chemotherapy, investigational agent, biologic agent or 
other anti-tumor agents.  Radiation therapy is also prohibited. 
Patients should be strongly discouraged from taking any “alternative” or “naturopathic” medications 
since these agents may interact with APVD.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
27 of 61
4.3.3 Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 4.2.2, 
[Table 3].  Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts should be 
made to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care.  The treatment guidelines are intended to be applied when the 
Investigator determines the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 5.2.2 for 
guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
When study interventions are administered in combination, attribution of an adverse event to a single 
component is likely to be difficult.  Therefore, while the investigator may attribute a toxicity event to 
pembrolizumab alone, or to the combination of other chemo drugs, for adverse events listed below, 
all interventions must be held according to the criteria below.
When study interventions are administered in combination, if the AE is considered immune-related, 
all interventions should be held according to recommended dose modifications.
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab 
in this study.

If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions.

If the toxicities do resolve and conditions are aligned with what is defined below, the  
combination of study therapies may be restarted at the discretion of the investigator. In 
these cases where the toxicity is attributed to the other chemotherapy combination or 
individual drugs, re-initiation of pembrolizumab as a monotherapy may be considered 
at the investigator’s discretion.
4.4
Participant Withdrawal/Discontinuation Criteria
Participants may discontinue study treatment at any time for any reason or be dropped from the study 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, a 
participant may be discontinued from study treatment by the investigator or the Sponsor if study 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
28 of 61
Specific details regarding procedures to be performed at study treatment discontinuation are provided 
in Section 7.1.4 – Other Procedures.
A participant must be discontinued from study treatment but continue to be monitored in the study for 
any of the following reasons:

The participant or participant’s legally acceptable representative requests to 
discontinue study treatment

Confirmed radiographic disease progression outlined in Appendix 3

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Unacceptable adverse experiences as described in Section 6.2.

The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.

The participant has a confirmed positive serum pregnancy test

Noncompliance with study treatment or procedure requirements

Recurrent Grade 2 pneumonitis

Completion of protocol treatment

The participant is lost to follow-up

Administrative reasons
4.5
Participant Replacement Strategy
Subjects who fail to complete study therapy will not be replaced.
4.6
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be provided so 
that appropriate adjustments to participant treatment can be made.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
29 of 61
5.0 STUDY FLOW CHART – PART A AND PART B
Required Studies
Pre-Entry
(within 4 weeks 
unless indicated 
otherwise)
Within 2 days 
prior to each 
dose8
Post Therapy4
Safety Follow-up 
Visit5
Follow-up6
Physical
History and Physical (H&P)
X
X1
X
X
Performance Status
X
X1
X
X
Clinical Disease Assessment
X
X1
X
Adverse Event Assessment
X
X1
X
X
Lab 
ESR, TSH, T3, T4, LDH
X7
X10
X
Complete blood count with differential9
X
X1
X
X
Comprehensive metabolic panel9
X
X1
X
X
Pregnancy test
X2
Radiology
Left Ventricular Ejection Fraction (LVEF)
X3
PET/CT
X11
X
Correlative Studies12
X
X
1. For Cycle 1 Day 1, pre-entry H&P, performance status, disease assessment and adverse event assessment may be used (these do not need 
to be repeated within 2 days) and labs done within 10 days are acceptable.  
2. Pregnancy test in women of childbearing potential.
3. EF must be >50% within 56 days.
4. Post therapy (interim PET for patients planning on receiving more than 2 total cycles) studies should be done as early as day 16 of cycle 2 
but prior to any additional antineoplastic therapy unless other objective evidence of progressive disease.  For patients who proceed with 
more than 2 cycles of therapy (Optional part A, mandatory 6 cycles for part B), an additional post therapy visit with additional PET/CT 
should be performed 28-35 days after the expected last dose of chemotherapy, which may also serve as the post treatment safety visit.
5. A safety follow up visit should be performed 28-35 days after last dose of study therapy is administered.  This may be an additional visit 
depending on the date of the post-therapy visit, but may be combined with the post-therapy visit if the windows overlap.
6. Follow-up after cycle 2 will be standard of care. Patient will be tracked for subsequent therapy, response, progression-free, and overall 
survival after completion of 2 cycles of therapy up to 5 years.  
7.  Patients must have an ESR, TSH, T3 and T4 performed within 14 days prior to registration.
8. Dose is defined as a day in which one receives any of the medications outlined in section 4.2
9. See Table 6 for list of components
10. LDH and ESR not required at Post Therapy or Safety follow up visit
11. PET/CT may be performed within 42 days.
12. Correlative studies may be carried out whenever possible and include PD1/PLDL1/PDL2 expression, MRD (e.g. Adaptive Clonoseq or 
similar) and cytokine monitoring.  This may include up to 10 unstained slides of diagnostic tissue or tissue block as well as up to 20 cc of 
whole blood and serum at the following (but not limited to) timepoints: baseline, cycle 2 day 1, cycle 3 day 1, and end of treatment.
Fred Hutch IRB
Approved 
10/18/2023


30
Protocol v7.0 dated 16Dec2022  
30 of 61
6.0 TRIAL PROCEDURES
6.1
Trial Procedures
The Trial Flow Chart - Section 5.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck 
for reasons related to participant safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
informed consent be obtained from the participant.  In these cases, such evaluations/testing will be 
performed in accordance with those regulations.
6.1.1 Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of the 
person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before participation in 
the trial.
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the participant must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The participant or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
participant’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements.
6.1.1.1
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial. 
Fred Hutch IRB
Approved 
10/18/2023


31
Protocol v7.0 dated 16Dec2022  
31 of 61
6.1.1.2
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the participant has enrolled in this study will be recorded separately and not listed as 
medical history.  
6.1.1.3
Prior and Concomitant Medications Review
6.1.1.3.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the participant within 28 days 
before starting the trial.  Treatment for the disease for which the participant has enrolled in this study 
will be recorded separately and not listed as a prior medication. 
6.1.1.3.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 6.1.2.1.
6.1.1.4
Disease Details and Treatments
6.1.1.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease status. 
6.1.1.4.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries.
6.1.1.4.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  
6.1.1.5
Assignment of Subject Number
Each subject will be assigned a unique subject identifier.
Fred Hutch IRB
Approved 
10/18/2023


32
Protocol v7.0 dated 16Dec2022  
32 of 61
6.1.2 Clinical Procedures/Assessments
6.1.2.1
Adverse Event (AE) Monitoring
Complete and timely reporting of adverse events (AEs) is required to ensure the safety of patients.  
Reporting requirements are determined by the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) 
of the adverse event.  The guidelines outlined in this section, as well as the specific direction on each 
report form must be followed.  The NCI Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) will be used to classify and grade toxicities.  
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Appendix 2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
6.1.2.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, 
6.1.2.3
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  
6.1.2.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 5.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
Fred Hutch IRB
Approved 
10/18/2023


33
Protocol v7.0 dated 16Dec2022  
33 of 61
6.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment as specified in 
the Trial Flow Chart.  
6.1.2.6
Tumor Imaging and Assessment of Disease
Tumor imaging consists of standard of care FDG-PET/CT of the chest, abdomen, and pelvis 
at baseline within 42 days of day 1 of cycle 1.  Post therapy (interim PET for those receiving 
more than 2 total cycles) imaging will consist of FDG-PET/CT of the chest, abdomen, and 
pelvis and should be performed as early as day 16 of cycle 2, but prior to any additional 
antineoplastic therapy.  Additional imaging studies may per performed at the discretion of the 
treating provider.
Assessment of Disease
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – response will be 
defined by standard NCI criteria (Lugano 2014) for lymphoid malignancies.
6.1.2.7
Tumor Tissue Collection and Correlative Studies Blood Sampling
Correlative studies may be carried out whenever possible for ctDNA testing. Blood samples will be 
collected in two to four 10 mL K2EDTA tubes at baseline, on cycle 2 day 1, and after cycle 2.  
Additional blood draws can be collected at the investigator’s discretion.  Additionally, up to 10 
unstained slides of diagnostic tissue or tissue block may also be collected.
6.1.3 Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below. 
Laboratory tests for hematology, chemistry, and others are specified in Table 6.  
Fred Hutch IRB
Approved 
10/18/2023


34
Protocol v7.0 dated 16Dec2022  
34 of 61
Table 6 Laboratory Tests
Complete blood count (CBC) 
with differential
Comprehensive metabolic panel
Other
Hematocrit
Albumin
Serum or urine β-human chorionic 
gonadotropin(β-hCG)†
Hemoglobin
Alkaline phosphatase
Total thriiodothyronine (T3)
Platelet count
Alanine aminotransferase (ALT)
Free tyroxine (T4)
WBC (total and differential)
Aspartate aminotransferase (AST)
Thyroid stimulating hormone (TSH)
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Erythrocyte Sedimentation Rate (ESR)
Absolute Neutrophil Count
Carbon Dioxide ‡
Absolute Lymphocyte Count
  (CO2 or biocarbonate)
Uric Acid
Calcium
Chloride
Blood for correlative studies
Glucose
 
 
Sodium
 
Total Bilirubin
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen


35
Protocol v7.0 dated 16Dec2022  
35 of 61
Laboratory tests for screening should be performed within 10 days prior to the first dose of treatment.  
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  
Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to 
each dose of trial treatment.
6.1.4 Other Procedures
6.1.4.1
Withdrawal/Discontinuation/Visit Requirements
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 6.2 - Assessing and 
Recording Adverse Events.  Visit requirements are outlined in Section 5.0 - Trial Flow Chart.   
Specific procedure-related details are provided above in Section 6.0 - Trial Procedures.
6.1.4.2
Screening
6.1.4.2.1 Screening Period
The screening period begins upon signing consent and prior to Cycle 1 Day 1 of study 
therapy. The screening period may last up to 42 days, which may be extended provided the 
patients re-signs a consent form.
6.1.4.3
Treatment Period
The treatment period includes APVD, administered every 28 days. Administration of study 
medications may be +/- 2 days of the expected date as outlined in section 2.2.  All other 
procedures should be performed per the Study Flow Chart. 
6.1.4.4
Post-Therapy Visit
Post therapy procedures should be performed per the Study Flow Chart and include Physical 
Exam, Laboratory assessments, and imaging studies.
6.1.4.5 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose 
of study treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All 
AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Participants with an AE of 
Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new 
anti-cancer therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or 
before initiation of a new anti-cancer treatment should also be followed and recorded.  \
Fred Hutch IRB
Approved 
10/18/2023


36
Protocol v7.0 dated 16Dec2022  
36 of 61
6.1.4.6 Follow-up Visits
Follow-up after Cycle 2 (Cycle 6 for part B) will be conducted per Standard of Care.  Patients will be 
tracked for subsequent therapy, response, progression-free, and overall survival up to 5 years.  
6.2
Assessing and Recording Adverse Events
Routine reporting is required for all grade 3, 4 and 5 adverse events.  Grade 1 or 2 AEs will not be 
captured or reported with the exception of ANC, platelet nadirs, or immune related adverse events. 
Routine reports include data after each cycle of therapy and 30 days after the last dose of study drugs, 
or until the patient receives an alternative anti-cancer therapy, whichever date comes first.   
Routine reporting will be conducted in accordance with FHCRC/Cancer Consortium IRB policies, 
applicable FDA regulations, and agreements with Merck.
6.2.1
Expedited Reporting 
Expedited reporting will be conducted in accordance with FHCRC/Cancer Consortium IRB policies, 
applicable FDA regulations.
6.3
Overdose and Reporting Requirements
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, the participant should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious 
Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without 
adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215-661-6229)
6.3.1 Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and infant exposure during breast feeding are not considered adverse events, it 
is the responsibility of investigators or their designees to report any pregnancy or lactation in a 
participant (spontaneously reported to them) that occurs during the study.
Fred Hutch IRB
Approved 
10/18/2023


37
Protocol v7.0 dated 16Dec2022  
37 of 61
Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed but 
before treatment allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.  All reported pregnancies must be followed to the 
completion/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 serious events (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 Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229)
6.3.1.1
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229).
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must 
be reported within 2 working days to Merck Global Safety if it causes the participant to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 2 working days to Merck 
Global Safety.
Events of clinical interest for this trial include:
1.  an overdose of Merck product, as defined in Section 6.3- Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or 
abnormal laboratory results. 
Fred Hutch IRB
Approved 
10/18/2023


38
Protocol v7.0 dated 16Dec2022  
38 of 61
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and 
an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, 
at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, 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 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
6.3.1.1.1 Evaluating Adverse Events
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022  
  
39 of 61
Table 7 Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days..


Protocol v7.0 dated 16Dec2022  
  
40 of 61
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause Merck product to be discontinued?
Relationship to 
Merck Product 
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE):
Exposure
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors


Protocol v7.0 dated 16Dec2022  
  
41 of 61
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Merck 
Product
(continued) 
Dechallenge
Was Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the participant re-exposed to Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship).
Yes, there is a reasonable 
possibility of Merck product 
relationship.
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause.


Protocol v7.0 dated 16Dec2022  
  
42 of 61
No, there is not a reasonable 
possibility of Merck product 
relationship
Participant did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.)


Protocol v7.0 dated 16Dec2022   
43 of 61
6.3.2 Sponsor Responsibility for Reporting Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s product 
that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is another important medical event 

Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious 
by Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety if it causes the participant to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety.
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be 
related to Merck product that is brought to the attention of the investigator at any time following 
consent through the end of the specified safety follow-up period specified in the paragraph above, or at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to Merck Global Safety.
All participants with serious adverse events must be followed up for outcome.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
44 of 61
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA.
7.0 STATISTICAL ANALYSIS PLAN
7.1
Statistical Analysis Plan
Part A:
The primary objective of this study is to estimate the safety of 2 cycles of APVD. Historical data 
regarding the tolerability of 2 cycles of ABVD are limited. In a recent trial of AVD+ brentuximab 
vedotin, 4 of 26 (~15%) patients were reported to be unable to complete treatment [Connors et al. 
2017]. treatment18. We will be more conservatively scoring treatment delay due to toxicity rather 
than inability to complete the entire treatment course. Thus, we will deem this regimen safe if 
>85% of patients are able to complete 2 cycles of APVD without a dose delay of >3 weeks. This 
will be employed as a stopping rule and serve as the primary endpoint. 
Operationally, the stopping rule will be activated if the lower limit of the 95% confidence interval 
of toxicity crosses 15%. Thus, the trial would stop if 4/10, 7/20, 8/25, or 9 of 30 had a dose delay 
of >3 weeks due to toxicity. 
If the stopping rule is activated the trial will be paused and the data reviewed to determine if the 
results can be explained by the patient population (e.g., older, more comorbidities) or by the 
toxicity of the regimen. A report will be drafted for IRB review to either close the trial, modify 
and continue the trial, or continue the trial in an unmodified fashion. Since the study is not 
statistically powered for efficacy evaluation, the sample size justification is based on clinical 
evaluation on safety. If we use the stopping rule if 30% patients were unable to complete treatment, 
then the 95% confidence interval for the assumed toxicity rate with 30 patients are 17% to 48%, 
which excluded 15% assumed rate. With smaller sample size, the width of the 95% CI will be 
larger, e.g. 15% to 52% for 20 patients, 16% to 50% for 25 patients, etc. The larger sample size 
will also lead to stable point estimation, so it will increase the chance for a more accurate 
observation. We anticipate that 30 patients will be required to reasonably estimate the safety of 
this regimen as defined above. Furthermore, assume the incidence rate of toxicity is around 15%, 
with sample size N=30, we will have more than 85% chance of observing more than two patients 
not finishing the trial and 99% chance of observing at least one such patient (see table 1) 
Probability to observe at least 1 or 3 events having a dose delay due to toxicity, estimated for 
different incidence rates and sample size
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
45 of 61
Sample Size
Incidence 
rate 
of 
toxicity 
PR (observe at 
least one events had a 
dose delay) 
PR (observe at 
least three events had a 
dose delay) 
30
0.1
96%
59%
30
0.15
99%
85%
25
0.1
93%
46%
25
0.15
98%
75%
20
0.1
88%
32%
20
0.15
96%
60%
In unpublished data, 28 patients have completed 2 cycles of APVD, and there were no delays in 
treatments of greater than 21 days in any of these patients. Therefore, even without information on 
the final 2 patients, it can be determined that the primary endpoint for part A of the study has been 
met.
Part B:
Based on the rationale outlined in the background section, we plan to enroll 20 additional patients 
in part B (for a total of 50 between part A and B). We will only accrue advanced stage patients 
(stage 3 or 4) for this portion of the study.
In part A, we have enrolled 29 patients, of whom 18 were stage 3 or 4. We expect the final patient 
in part A will be advanced stage, and therefore we expect to have 19 total advanced stage patients 
in Part A. When combined with expected accrual of 20 patients in Part B, we expect to have 39 
total advanced stage patients that are evaluable for efficacy data.
Given our concerns with PET-based assessments, we will analyze the 39 advanced patients for 
efficacy by estimating 1-year EFS. An event will be defined as progression, biopsy proven 
recurrence, initiation of next line of chemotherapy, or death. The benchmark to deem this regimen 
as potentially efficacious will be 1-year EFS of 85% for this population3 (intermediate between 
the more commonly used ABVD and the more toxic but less commonly used brentuximab vedotin 
+ AVD). Towards this end, we shall consider an observed 1-year EFS among the 39 patients of at 
least 0.85 (33 or more of 39) to be potentially efficacious and warrant further study of the current 
regimen (note that this will not necessarily imply a statistically significant improvement on this 
benchmark). The decision will also take into consideration secondary endpoints. The table below 
summarizes the probability of observing a 1-year EFS of at least 85% under a variety of assumed-
true 1-year EFS values.   
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
46 of 61
Assumed-true 
1-year EFS
Probability of observed 1-year 
EFS of at least 85%
75%
0.11
80%
0.31
85%
0.63
90%
0.91
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
8.1
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations.
Pembrolizumab will be provided by Merck as summarized in Table 8.
Table 8 Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
8.2
Packaging and Labeling Information
Supplies will be labeled in accordance with regulatory requirements.
8.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
8.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
8.5
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to and returned by the participants and the amount remaining at the 
conclusion of the trial. 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
47 of 61
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept.
9.0  DATA AND SAFETY MONITORING PLAN
Ongoing trial oversight is carried out by the Principal Investigator and study staff. These 
individuals will communicate on a regular basis to review recently acquired data and 
adverse events. The data recorded within the research charts and protocol database is 
compared with the actual data that is available from the medical record and/or clinical 
histories.  Data detailed in the research case report forms includes the nature and severity 
of all toxicities, which are also reported as described above.  
Institutional support of trial monitoring will be in accordance with the FHCRC/UW Cancer 
Consortium Institutional Data and Safety Monitoring Plan.  Under the provisions of this 
plan, FHCRC Clinical Research Support coordinates monitoring for data accuracy and 
compliance by consultants, contract research organizations, or FHCRC employees 
unaffiliated with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous 
visits per the institutional DSMP. 
In addition, protocols are reviewed at least annually and as needed by a the Consortium 
Data Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee 
(SRC) and the FHCRC/Cancer Consortium Institutional Review Board (IRB).  The review 
committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients.  
The IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects.  Approval of committees as 
applicable is necessary to continue the study.
The trial will comply with the standard guidelines set forth by these regulatory committees 
and other institutional, state and federal guidelines.
The IRB has the authority to suspend or terminate the study should it be deemed necessary.
9.1
 RECORDS
Research staff under the supervision of the investigators will maintain case report forms 
and secured databases on the relevant clinical and laboratory data.  Records maintained in 
investigators' offices will be secured with access limited to study personnel. Authorization 
for access to medical records will be obtained from all patients in accordance with 
provisions of the Health Insurance Portability and Accountability Act (HIPAA).
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
48 of 61
9.2
   REGULATORY RESPONSIBILITIES OF SPONSOR-INVESTIGATOR
The Sponsor-Investigator will ensure that the study is conducted in accordance with all 
applicable institutional, state, and federal regulatory requirements, including, but not 
limited to: compliance with requirements for IRB and other regulatory approvals, 
monitoring responsibilities, reporting obligations, and compliance with standards for 
written informed consent from all patients entering the study. In addition, the sponsor will 
ensure oversight of the study via data and safety monitoring as described above.
10.0   REFERENCES
1. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination 
chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and 
imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252.) 
2. Vassilakopoulos TP, Johnson PW. Treatment of advanced-stage Hodgkin lymphoma. 
Semin Hematol. 2016 Jul;53(3):171-9. doi: 10.1053/j.seminhematol.2016.05.006. Epub 
2016 May 12.
3. Boleti E1, Mead GM. ABVD for Hodgkin's lymphoma: full-dose chemotherapy without 
dose reductions or growth factors. Ann Oncol. 2007 Feb;18(2):376-80.
4. Alinari L, Blum KA. How I treat relapsed classical Hodgkin lymphoma after autologous 
stem cell transplant. Blood. 2016 Jan 21;127(3):287-95.
5. Hirsch A, Vander Els N, Straus DJ, Gomez EG, Leung D, Portlock CS, Yahalom J. 
Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on 
pulmonary function and symptoms in early-stage Hodgkin's disease. J Clin Oncol. 
1996;14(4):1297.
6. Horning SJ, Adhikari A, Rizk N, Hoppe RT, Olshen RA. Effect of treatment for 
Hodgkin's disease on pulmonary function: results of a prospective study. J Clin Oncol. 
1994;12(2):297.
7. Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE, Ansell SM. Bleomycin 
Pulmonary Toxicity Has a Negative Impact on the Outcome of Patients With Hodgkin's 
Lymphoma. J Clin Oncol. 2005 Oct 20;23(30):7614-20. Epub 2005 Sep 26. 
8. Behringer K, Goergen H, Hitz F, Zijlstra JM, Greil R, Markova J, Sasse S, Fuchs M, 
Topp MS, Soekler M, Mathas S, Meissner J, Wilhelm M, Koch P, Lindemann HW, 
Schalk E, Semrau R, Kriz J, Vieler T, Bentz M, Lange E, Mahlberg R, Hassler A, 
Vogelhuber M, Hahn D, Mezger J, Krause SW, Skoetz N, Böll B, von Tresckow B, Diehl 
V, Hallek M, Borchmann P, Stein H, Eich H, Engert A; German Hodgkin Study Group; 
Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse 
Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen 
in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-
label, randomised, non-inferiority trial. Lancet. 2015 Apr 11;385(9976):1418-27.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
49 of 61
9. Canellos GP, Duggan D, Johnson J, Niedzwiecki D. How important is bleomycin in the 
adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol. 2004 Apr 
15;22(8):1532-3. 
10. Yamamoto R1, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, Kondo T, 
Ohmori K, Kurata M, Hayashi T, Uchiyama T. PD-1-PD-1 ligand interaction contributes 
to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 
2008;111:3220–3224.
11. Chen BJ1, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, 
Freeman GJ, Shipp MA, Rodig SJ.PD-L1 expression is characteristic of a subset of 
aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 
2013;19:3462–3473 
12. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer. 2012 Mar 22;12(4):252-64.
13. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or 
refractory Hodgkin's lymphoma. N Engl J Med. 2015 Jan 22;372(4):311-9. doi: 
10.1056/NEJMoa1411087. PMID: 25482239
14. Armand et al. Programmed Death-1 Blockade With Pembrolizumab in Patients With 
Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure.J Clin Oncol. 2016 
Jun 27. pii: JCO673467. [e pub]
15. Chen et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for 
Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol. 2017 Apr 
25:JCO2016721316. doi: 10.1200/JCO.2016.72.1316. [Epub ahead of print]
16. Rizvi NA, Mazieres J, Planchard D, et al. Activity and safety of nivolumab, an anti- PD-1 
immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-
cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 
2015;16(3):257-265
17. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: 
results of a randomized phase II trial. J Clin Oncol. 2014;33(13):1430-1437.
18. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and 
long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 
2014;32(10):1020-1030
19. Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, Chow 
LQ, Gerber DE, Laurie SA, Goldman JW, Shepherd FA, Chen AC, Shen Y, Nathan FE, 
Harbison CT, Antonia S. Nivolumab in Combination With Platinum-Based Doublet 
Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J 
Clin Oncol. 2016 Jun 27. [Epub ahead of print]
20. Lara et al. Combination checkpoint immunotherapy and cytotoxic chemotherapy: 
Pembrolizumab (Pembro) plus either docetaxel or gemcitabine in patients with advanced 
or metastatic urothelial cancer. J Clin Oncol 35, 2017 (suppl 6S; abstract 398)
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
50 of 61
21. Gadgeel et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for 
advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol 34, 2016 (suppl; abstr 
9016)
22.  Langer et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, 
non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label 
KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-
2045(16)30498-3. Epub 2016 Oct.
23. Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, Huebner D, 
Ansell SM. Brentuximab vedotin combined with ABVD or AVD for patients with newly 
diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet 
Oncol. 2013 Dec;14(13):1348-56.
24. Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
25. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.
26. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
28. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits 
B cell receptor-mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
29. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity 
2004;20:337-47.
30. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate 
with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 
2004;173:945-54.
31. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits 
T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and 
downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.
32. Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
33. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et 
al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol 
Cell Biol 2005;25(21):9543-53.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
51 of 61
34. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
35. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet 
Oncol. 2017;18(3):e143-e152. Epub 2017 Mar 2.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
52 of 61
11.0 APPENDICES
Appendix 1: ECOG 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 (e.g., 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.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
53 of 61
Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
54 of 61
Appendix 3:  Response Criteria: “The Lugano Classification” 38
Response 
and 
Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all 
of the following)
Score 1, 2, or 3* with or without a residual 
mass on 5PS†
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi
Lymph nodes and 
extralymphatic 
sites
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (eg, with chemotherapy or 
myeloid 
colony-stimulating 
factors), 
uptake may be greater than normal 
mediastinum 
and/or 
liver. 
In 
this 
circumstance, 
complete 
metabolic 
response may be inferred if uptake at sites 
of initial involvement is no greater than 
surrounding normal tissue even if the 
tissue has high physiologic uptake
No extralymphatic sites of disease
    
Nonmeasured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
 New lesions
None
None
 Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal 
by 
morphology; 
if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the 
following)
    Lymph 
nodes 
and 
extralymphatic 
sites
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size
≥ 50% decrease in SPD of up to 6 
target 
measurable 
nodes 
and 
extranodal sites
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
55 of 61
Response 
and 
Site
PET-CT–Based Response
CT-Based Response
At interim, these findings suggest 
responding disease
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value
At end of treatment, these findings 
indicate residual disease
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
    
Nonmeasured 
lesions
Not applicable
Absent/normal, regressed, but no 
increase
Organ 
enlargement
Not applicable
Spleen must have regressed by > 
50% in length beyond normal
 New lesions
None
None
 Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with 
reactive 
changes 
from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan
Not applicable
No response or 
stable disease
No metabolic response
Stable disease
Target 
nodes/nodal 
masses, 
extranodal 
lesions
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or 
end of treatment
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
56 of 61
Response 
and 
Site
PET-CT–Based Response
CT-Based Response
    
Nonmeasured 
lesions
Not applicable
No 
increase 
consistent 
with 
progression
Organ 
enlargement
Not applicable
No 
increase 
consistent 
with 
progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Progressive metabolic disease
Progressive disease requires at 
least 1 of the following
    
Individual target 
nodes/nodal 
masses
Score 4 or 5 with an increase in intensity 
of uptake from baseline and/or
PPD progression:
    
Extranodal 
lesions
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment
An individual node/lesion must be 
abnormal 
with:
LDi 
> 
1.5 
cm 
and
Increase by ≥ 50% from PPD nadir 
and
An increase in LDi or SDi from 
nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline (eg, a 15-
cm spleen must increase to > 16 
cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline
New or recurrent splenomegaly
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
57 of 61
Response 
and 
Site
PET-CT–Based Response
CT-Based Response
    
Nonmeasured 
lesions
None
New or clear progression of 
preexisting nonmeasured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, 
its presence must be unequivocal 
and must be attributable to 
lymphoma
Assessable disease of any size 
unequivocally 
attributable 
to 
lymphoma
 Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement

Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; 
IHC, immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic 
resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi 
and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the 
product of the perpendicular diameters for multiple lesions.

↵* A score of 3 in many patients indicates a good prognosis with standard treatment, 
especially if at the time of an interim scan. However, in trials involving PET where de-
escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 
two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include 
those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, 
or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, 
dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that 
would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that 
cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites 
(eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
58 of 61
with complete metabolic response, but should be no higher than surrounding normal 
physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid 
growth factors).

↵† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > 
mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver 
and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
59 of 61
Appendix 4: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment.
Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if they agree to 
one of the following during protocol treatment and for 120 days after last dose: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long 
term and persistent basis) and agree to remain abstinent
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year as 
described in Table 9 when having penile-vaginal intercourse with a woman of childbearing potential 
who is not currently pregnant.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration.
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
60 of 61
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use two forms of 
birth control consistently and correctly during the protocol treatment and for 120 days after last dose. 
Subjects may use hormonal contraception, the barrier method or a highly effective method of 
contraception that has a low user dependency as outlined in Table 9 below. 
Table 9 Highly Effective Contraceptive Methods That Have Low User Dependency
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant a, b
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation.
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the treatment 
period and for at least [120 days, corresponding to time needed to eliminate study treatment plus 30 
days for study treatments with genotoxic potential] after the last dose of study treatment.  
Fred Hutch IRB
Approved 
10/18/2023


Protocol v7.0 dated 16Dec2022   
61 of 61
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test and in 
accordance with local requirements.  When applicable this test should be repeated a maximum of 24-
hours before the first dose/vaccination.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when pregnancy 
is otherwise suspected.
1.
Disis ML: Immune regulation of cancer. J Clin Oncol 28:4531-8, 2010
2.
Straus DJ, Długosz-Danecka M, Alekseev S, et al: Brentuximab vedotin with 
chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 
study. Blood 135:735-742, 2020
3.
Connors JM, Jurczak W, Straus DJ, et al: Brentuximab Vedotin with Chemotherapy 
for Stage III or IV Hodgkin's Lymphoma. N Engl J Med, 2017
Fred Hutch IRB
Approved 
10/18/2023