Phase II Study of Second- Line Pembrolizumab Plus GVD for Relapsed or Refractory Hodgkin Lymphoma

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase

Enrolling

Phase 2

Conditions

Relapsed or Refractory Hodgkin Lymphoma

Hodgkin Lymphoma

Treatments

Drug: vinorelbine

Drug: gemcitabine

Drug: pembrolizumab

Drug: liposomal doxorubicin

Procedure: Stem cell mobilization and collection

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT03618550

18-160

Details and patient eligibility

About

The purpose of this study is to test any good and bad effects of the study drug, pembrolizumab, in combination with GVD in the treatment of Hodgkin lymphoma.

Enrollment

257 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Histologic diagnosis of classical Hodgkin's lymphoma. Primary refractory or relapsed disease proven by biopsy at enrolling institution.
Stage I-III Hodgkin lymphoma (part 3)
Relapse or refractory disease following 1 line of multi-agent chemotherapy (not including pembro-GVD).
Eligible for HDT/ASCT
Achieved complete response (Deauville 3 or better) per clinical review following 2 cycles of pembro-GVD
Be willing and able to provide written informed consent/assent for the trial.
Be ≥ 18 years of age on day of signing informed consent.
Have measurable disease based on Lugano 2014 criteria
Have a performance status of 0 or 1 on the ECOG Performance Scale
Demonstrate adequate organ function as defined in table below
Demonstrate adequate organ function as defined in table below. Hematological
Absolute neutrophil count (ANC) ≥1000 /mcL
Platelets ≥50,000 / mcL
Hemoglobin ≥8 g/dL Renal
Serum creatinine OR ≤1.5 X upper limit of normal (ULN) OR
Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic
Serum total bilirubin ≤ 1.5 X ULN OR ≤ 3 X ULN for subjects with liver metastases
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases Pulmonary
Hemoglobin-adjusted diffusing capacity for carbon monoxide ≥50% (If unadjusted DLCO is >/= 50% then there is no need to calculate adjusted) Cardiac
Ejection fraction ≥45% Coagulation
International normalized ratio (INR) OR prothrombin time (PT), Activated partial thromboplastin time (aPTT): ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
Female subject of childbearing potential should have a negative urine or serum pregnancy within 2 weeks prior to receiving the first dose of study medication. On the day of planned treatment, if a blood pregnancy test has not been performed within the two week window, a stat pregnancy test (urine or blood) should be performed and the results reviewed before treatment is begun.
Female subjects of childbearing potential must be willing to use an adequate method of contraception (see details in section 11.4.3).
Male subjects of childbearing potential must agree to use an adequate method of contraception.(see details in section 11.4.3).
HIV-infected participants must have well-controlled HIV on ART, defined as:
- Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening
- Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening
- It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months.
- Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study
Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible.

Exclusion criteria

Received more than 1 prior treatment (combined modality therapy represents 1 treatment) for Hodgkin Lymphoma
Known pregnancy or breast-feeding.
- Breast-feeding should be discontinued prior to treatment initiation.
Medical illness unrelated to Hodgkin's Lymphoma, which, in the opinion of the attending physician and/or principal investigator, makes participation in this study inappropriate.
Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Has known active HIV, Hepatitis B (e.g., Hepatitis B PCR positive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
Has an active infection requiring systemic therapy.
Has not adequately recovered from major surgery or has ongoing surgical complications
Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had an allogeneic hematopoietic transplant greater than 5 years ago are eligible as long as there are no symptoms of GVHD.)
Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Single Group Assignment

Masking

None (Open label)

257 participants in 6 patient groups

Safety Window and DLT definition (Part 1)

Experimental group

Description:

Initially, 6 patients will be treated on the safety portion of the study and observed for dose limiting toxicities (DLTs). If 1 or fewer patients experience dose\[1\]limiting toxicity (DLT), enrollment onto the study will proceed according to a phase II, Simon 2- stage design.

Treatment:

Procedure: Stem cell mobilization and collection

Drug: liposomal doxorubicin

Drug: gemcitabine

Drug: pembrolizumab

Drug: vinorelbine

Safety monitoring beyond after completion of safety window (PART 1)

Experimental group

Description:

During the phase II portion of the study, patients will continue to be monitored for DLTs, adverse events, and events of interest throughout treatment with pembrolizumab-GVD, ASCT (part 1, if applicable), and 100 days following the last dose of pembrolizumab. Total planned enrollment is 39 patients

Treatment:

Procedure: Stem cell mobilization and collection

Drug: liposomal doxorubicin

Drug: gemcitabine

Drug: pembrolizumab

Drug: vinorelbine

Autologous Stem Cell Transplant (ASCT) (PARTS 1 and 3)

Experimental group

Description:

Stem cell mobilization and collection will be performed as per institutional guidelines after 2-4 cycles of pembrolizumab-GVD.

Treatment:

Procedure: Stem cell mobilization and collection

Drug: liposomal doxorubicin

Drug: gemcitabine

Drug: pembrolizumab

Drug: vinorelbine

Pembrolizumab maintenance (PART 2)

Experimental group

Description:

In part 2 of the study, patients who achieve complete response after 4 cycles of pembrolizumab\[1\]GVD will receive single-agent pembrolizumab for 13 cycles, which will begin 3-5 weeks after cycle 4 of pembrolizumab-GVD.

Treatment:

Procedure: Stem cell mobilization and collection

Drug: liposomal doxorubicin

Drug: gemcitabine

Drug: pembrolizumab

Drug: vinorelbine

Pembrolizumab maintenance, third-line therapy, and HDT/ASCT (PART 3)

Experimental group

Description:

In part 3 of the study, patients who achieve complete response after 2 cycles of pembrolizumab\[1\]GVD will be randomized to either consolidation with autologous stem cell transplant (after an additional optional 1-2 cycles of pembro-GVD) or 2 cycles of pembro-GVD followed by single agent pembrolizumab maintenance for 13 cycles.

Treatment:

Procedure: Stem cell mobilization and collection

Drug: liposomal doxorubicin

Drug: gemcitabine

Drug: pembrolizumab

Drug: vinorelbine

Involved-site radiation therapy (ISRT) (PART 3)

Experimental group

Description:

Patients with limited sites of disease prior to initiation of pembro-GVD are eligible to receive ISRT prior to ASCT with pembrolizumab maintenance.

Treatment:

Procedure: Stem cell mobilization and collection