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Vinblastine Sulfate

Jane Winter, M.D.

The purpose of this research study is to evaluate a new drug pembrolizumab in combination with chemotherapy, for the treatment of newly diagnosed Hodgkin lymphoma. The chemotherapy regimen is called AVD and includes three drugs: adriamycin, vinblastin, dacarbazine. Pembrolizumab is currently FDA approved for the treatment of some patients with melanoma, lung cancer and head and neck cancer, but has not yet been approved for the treatment of Hodgkins Lymphoma. The AVD regimen of chemotherapy is currently FDA approved for the treatment of newly diagnosed Hodgkin lymphoma, but has not yet been investigated in combination with pembrolizumab for this disease. For patients who have a new diagnosis of Hodgkins Lymphoma, multi-agent chemotherapy is recommended. Also, for patients who do not have a complete response to chemotherapy (meaning there is still evidence of disease on PET scans performed at the end of treatment), radiation is sometimes recommended. Furthermore, the rare patient who relapses after chemotherapy requires treatment with high dose chemotherapy and a transplant.

PRIMARY OBJECTIVES:

I. Assess the percent of patients who achieve a complete response (CR) to single-agent pembrolizumab induction, among patients with classical Hodgkin lymphoma (cHL) using Lugano 2014 criteria., as measured at PET #2.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of pembrolizumab in combination with chemotherapy in the frontline setting.

II. Determine the three-year progression free survival (PFS) and overall survival (OS) for patients \< 60 with early non-bulky disease, and elderly patients (all stages) treated with pembrolizumab with doxorubicin hydrochloride (Adriamycin), (bleomycin), vinblastine sulfate, dacarbazine (A\[B\]VD) in the frontline treatment of patients with cHL.

III. Determine the extent of fludeoxyglucose F-18 (FDG) uptake, using a semi-quantitative approach (e.g., Deauville score), after pembrolizumab induction, and after subsequent chemotherapy.

TERTIARY OBJECTIVES:

I. To characterize PD-1 pathway specific expression and correlate with response.

II. To characterize serum biomarkers of immune and inflammatory response during treatment.

III. To characterize levels of soluble PD-L1 related to treatment with pembrolizumab.

IV. To characterize T-lymphocyte subset changes to treatment with pembrolizumab.

V. To investigate the prevalence and clinical correlation of chromosome 9p24.1 alterations for this population.

OUTLINE:

INITIATION: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET/computed tomography (CT) scans before the start of pembrolizumab and after 3 courses.

AVD: Within 21 days after final dose of pembrolizumab, patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, and dacarbazine IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo a final FDG-PET/CT scan on day 117-120 or 26-29 of course 2. Patients with stage I/II disease with a CR continue treatment for up to 2 courses. Patients with stage III/IV disease with a CR or age \>= 60 with stage III/IV disease with any response continue treatment for up to 4 courses.

CONSOLIDATION: Patients age \>= 60 with stage III/IV disease who received \< 6 courses of AVD or patients age \>= 60 with DV 4-5 on FDG-PECT/CT scan receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

PET-Directed Therapy With Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Classical Hodgkin Lymphoma

Phase II Study of PET-Directed Frontline Therapy With Pembrolizumab and AVD for Patients With Classical Hodgkin Lymphoma

To assess the primary objective of response rate following PET #2 performed after 3 doses of pembrolizumab. PET response will be assessed using the Lugano Criteria (2014) which recommends the 5 point Deauville score for assessing response. The Deauville five-point scale is an internationally-recommended scale for routine clinical reporting and clinical trials using FDG PET-CT in the initial staging and assessment of treatment response in Hodgkin lymphoma (HL). Patients with a Deauville score of 1-3 will be considered a complete response.

Deauville criteria is defined as follows:

1. No residual uptake
2. Slight uptake, but below blood pool (mediastinum)
3. Uptake above mediastinum, but below or equal to uptake in the liver
4. Uptake slightly to moderately higher than liver
5. Markedly increased uptake or any new lesions

Patients will be evaluable for response assessment if they have received at least one dose of pembrolizumab.

To assess safety and tolerability, all adverse events will be summarized in terms of type, grade, timing and attribution to treatment and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE version 4.03).

PFS for elderly patients will be measured.

OS for elderly patients will be evaluated.

Evaluate the extent of FDG uptake by assessing PET scans to determine a Deauville score.

National Cancer Institute (NCI)

Merck Sharp & Dohme LLC

Northwestern University

Principal Investigator

Adverse event data shown below includes all events collected and available up until March 23rd 2020 for the study. Data collected includes the highest grade of the event experienced for each participant, and thus includes some serious adverse event data. Adverse event data

All patients get 3 cycles (21-days each) of pembrolizumab (PEM) induction, then a PET-CT (PET#2). PET#2 required for primary endpoint analysis. Patients evaluable for response assessment if they had at least one dose of PEM.

After, all patients get 2 cycles (28-days each) of AVD (doxorubicin, vinblastine, dacarbazine), followed by an interim PET-CT (PET#3) for response analysis.

Depending on age, stage, and PET#3 results per Deauville (DV) Score, patients get additional 2-4 cycles of AVD, or AVD and escBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) + radiotherapy (RT). Then, patients will have a PET-CT (PET#4) or a CT (CT if Stage I/II disease and negative for PET#3).

Patients under 60 go to survival follow-up. Patients over 60 go to survival follow-up or 1-2 years of PEM consolidation based on bulky vs non bulky disease, results of the PET#3, and the number of AVD cycles received.

See schema for details.

Treatment: Pembrolizumab and AVD Chemotherapy Guided by PET-CT

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Low stage number = less disease involvement. I: single lymph node (LN) region or lymphoid structure. II: two or more LN regions or LN structures on the same side of the diaphragm. III: LN regions or lymphoid structures on both sides of the diaphragm. IV: Diffuse or dissemination of one or more extranodal organs or tissue beyond, with or without associated LN involvement. \*A/B to indicate the absence (A) or presence (B) of the systemic symptoms of significant unexplained fever, night sweats, or unexplained weight loss exceeding 10% of body weight during 6 months prior to diagnosis.

Disease Stage

Per Protocol, bulky disease is a mass \>10 cm.

Bulky vs Non-Bulky Disease

Jane N. Winter, M.D.

Complete Response (CR) With Pembrolizumab Treatment Alone

Incidence of Adverse Events

Progression Free Survival (PFS) for Patients <60

PFS for Elderly Patients

Overall Survival (OS) for Patients <60

OS for Elderly Patients

FDG Uptake

PFS is defined as the number of patients that are progression/relapse free at the time of treatment completion (3 cycles of pembrolizumab and up to 6 cycles of AVD).

Progressive or relapse disease is defined as of the following:

Appearance of any new lesion more than 1.5 cm in any axis during treatment, even if other lesions are decreasing in size.

At least a 50% increased from nadir in the sum of the product of the diameter (SPD) of any previously involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be considered progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by at least 50% and to a size of more than 1.5 x 1.5 cm or more than 1.5 cm in the long axis.

At least a 50% increase in the longest diameter of any single previously identified node more than 1.0 cm in its short axis.

Lymphoma confirmed by repeat biopsy.

Progression Free Survival (PFS) at Treatment Completion

Overall survival will be defined as the number of patients that are alive at the time of treatment completion (3 cycles of pembrolizumab and 2-6 cycles of AVD)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PET-Directed Therapy With Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Classical Hodgkin Lymphoma	NCT03226249	Classical Hodgk... Lymphocyte-Depl... Lymphocyte-Rich... Mixed Cellulari... Nodular Scleros...	Computed Tomogr... Dacarbazine Doxorubicin Hyd... Fludeoxyglucose... Laboratory Biom... Pembrolizumab Positron Emissi... Vinblastine Sul...	18 Years -	Northwestern University
PET-Directed Therapy With Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Classical Hodgkin Lymphoma	NCT03226249	Classical Hodgk... Lymphocyte-Depl... Lymphocyte-Rich... Mixed Cellulari... Nodular Scleros...	Computed Tomogr... Dacarbazine Doxorubicin Hyd... Fludeoxyglucose... Laboratory Biom... Pembrolizumab Positron Emissi... Vinblastine Sul...	18 Years -	Northwestern University

Spots Global Cancer Trial Database for mixed cellularity classical hodgkin lymphoma