Second-Line Pembrolizumab in Combination with Gemcitabine, Vinorelbine, and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients with Relapsed or Refractory Hodgkin Lymphoma
This phase II trial studies the side effects and how well pembrolizumab in combination with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin hydrochloride work in treating patients with Hodgkin lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as gemcitabine, vinorelbine, and pegylated liposomal doxorubicin hydrochloride, 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. Giving pembrolizumab, gemcitabine, vinorelbine, and pegylated liposomal doxorubicin hydrochloride may work better at treating Hodgkin lymphoma.
Inclusion Criteria
- Histologic diagnosis of classical Hodgkin’s lymphoma. Primary refractory or relapsed disease proven by biopsy at enrolling institution.
- PART 3: Stage I-III Hodgkin lymphoma.
- Relapse or refractory disease following 1 line of multi-agent chemotherapy (not including pembro-GVD).
- Eligible for high dose therapy (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.
- PET scan before initiating pembro-GVD has measurable disease based on Lugano 2014 criteria.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
- Absolute neutrophil count (ANC) >= 1000 /mcL. * Lab values for eligibility should be based upon labs prior to cycle 1 treatment of Pembro-GVD
- Platelets >= 50,000 / mcL. * Lab values for eligibility should be based upon labs prior to cycle 1 treatment of Pembro-GVD
- Hemoglobin >= 8 g/dL. * Lab values for eligibility should be based upon labs prior to cycle 1 treatment of Pembro-GVD
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (estimated glomerular filtration rate [eGFR] can also be used in place of creatinine clearance) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN. * Lab values for eligibility should be based upon labs prior to cycle 1 treatment of Pembro-GVD
- Serum total bilirubin =< 1.5 X UL OR =< 3 X ULN for subjects with liver metastases. * Lab values for eligibility should be based upon labs prior to cycle 1 treatment of Pembro-GVD
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases. * Lab values for eligibility should be based upon labs prior to cycle 1 treatment of Pembro-GVD
- Hemoglobin-adjusted diffusing capacity for carbon monoxide >= 50%. (If unadjusted carbon monoxide diffusing capability test [DLCO] is >= 50% then there is no need to calculate adjusted.)
- Ejection fraction >= 45%.
- 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.
- Male subjects of childbearing potential must agree to use an adequate method of contraception.
- HIV-infected participants must have well-controlled HIV on antiretroviral therapy (ART), defined as: * Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm^3 at the time of screening. * Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 copies/mL or the lower limit of quantification (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 prior to receiving pembro-GVD.
- 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 an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- Has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients.
- 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Has known active hepatitis B (e.g., hepatitis B polymerase chain reaction [PCR] positive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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 graft-versus-host disease [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.
Additional locations may be listed on ClinicalTrials.gov for NCT03618550.
Locations matching your search criteria
United States
Florida
Miami
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
PRIMARY OBJECTIVES:
I. Establish the safety of pre-autologous stem-cell transplantation (ASCT) pembrolizumab plus gemcitabine, vinorelbine, and pegylated liposomal doxorubicin hydrochloride (GVD) for relapsed/refractory Hodgkin lymphoma. (Part 1, Safety Window)
II. Evaluate the complete response rate to pembrolizumab plus GVD in relapsed/refractory Hodgkin lymphoma. (Part 1, Phase II)
III. Evaluate the 2-year progression free survival (PFS) rate of complete responders to pembrolizumab plus GVD in relapsed/refractory Hodgkin lymphoma on a 13-cycle pembrolizumab maintenance regimen (Part 2).
IV. Assess freedom from disease at 5 years post-randomization. (Part 3)
SECONDARY OBJECTIVES:
I. Evaluate partial response and minor response rate to pembrolizumab plus GVD in relapsed/refractory Hodgkin lymphoma. (Part 1 and Part 2)
II. Evaluate progression free survival and overall survival for patients receiving pembrolizumab-GVD followed by ASCT. (Part 1 and Part 2)
III. Evaluate 2-year progression free survival and overall survival rates for patients receiving pembrolizumab-GVD followed by 13 cycles of pembrolizumab maintenance. (Part 1 and Part 2)
IV. Evaluate treatment response according to lymphoma response to immunomodulatory therapy criteria (LYRIC) criteria. (Part 1 and Part 2)
V. Assess percent of transplants avoided on cohort 3B. (Part 3)
VI. Assess treatment related toxicity for pembrolizumab maintenance regimen. (Part 3)
VII. Assess 5-year overall survival. (Part 3)
VIII. Assess 5-year progression-free survival. (Part 3)
IX. Assess 5-year time to progression. (Part 3)
X. Document any non-specified additional treatments patients receive and subsequent disease outcomes. (Part 3)
EXPLORATORY OBJECTIVES:
I. Assess association between serum TARC (Thymus and activation-regulated chemokine/CCL17) levels and progression free survival and achievement of complete response to therapy. (Part 1 and Part 2)
II. Assessment of quantitative fludeoxyglucose F 18 (FDG) positron emission tomography (PET) metrics, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), at baseline, after 2 cycles, and following 4 cycles of treatment and association between complete response to treatment and progression free survival. (Part 1 and Part 2)
III. Assessment of tumor-specific cell-free deoxyribonucleic acid (DNA) at baseline, after 2 cycles and 4 cycles of pembrolizumab plus GVD, cycles 10 and 17 of pembrolizumab maintenance, and 3 and 9 months following ASCT/maintenance and association between complete response to treatment and progression free survival. (Part 1 and Part 2)
IV. Evaluate association between expression of major histocompatibility complex (MHC)-I, MHC-II, beta-2 microglobulin, and 9p24.1 amplification by Reed-Sternberg cells and progression free survival and achievement of complete response to therapy. (Part 1 and Part 2)
V. Assess association between serum TARC (thymus and activation-regulated chemokine/CCL17) and tumor-specific cell-free DNA levels and post-maintenance outcomes among patients in Cohort 3A and 3B. (Part 3)
VI. Assess association between pre-transplant tumor-specific cell-free DNA and post- transplant outcomes. (Part 3)
VII. Assess association of clonal hematopoiesis with post-transplant therapy-related myeloid neoplasm (t-MN). (Part 3)
OUTLINE:
PART 1: Patients receive pembrolizumab intravenously (IV) on day 1, gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin hydrochloride IV on days 1 and day 8, and pegfilgrastim subcutaneously (SC) on day 9. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo ASCT. Patients who do not achieve a complete response (CR) after 2 cycles receive an additional 2 cycles, before undergoing ASCT.
PART 2 (EXPANSION COHORT): Patients receive pembrolizumab IV on day 1, gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin hydrochloride IV on days 1 and day 8, and pegfilgrastim SC on day 9. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve a CR after 4 cycles receive an additional 13 cycles of maintenance pembrolizumab.
PART 3: Patients receive pembrolizumab, gemcitabine, vinorelbine and pegylated liposomal doxorubicin hydrochloride and pegfilgrastim as in Parts 1 and 2. Patients who achieve CR after 2 cycles of pembrolizumab and GVD are randomized to 1 of 2 arms.
ARM I: Patients may optionally receive pembrolizumab, gemcitabine, vinorelbine and pegylated liposomal doxorubicin hydrochloride and pegfilgrastim for 2 additional cycles. Patients then undergo ASCT.
ARM II: Patients receive pembrolizumab, gemcitabine, vinorelbine and pegylated liposomal doxorubicin hydrochloride and pegfilgrastim for 2 additional cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve a CR after 4 cycles receive an additional 13 cycles of maintenance pembrolizumab. Patients with limited sites of disease or who have nodal-based disease may also receive involved-site radiation therapy (ISRT) before or during maintenance pembrolizumab per discretion of the treating physician. Patients who experience disease progression during or after maintenance pembrolizumab may receive any of the following third-line treatments per treating physician choice: 1) carboplatin, etoposide and ifosfamide (ICE regimen); 2) brentuximab vedotin + ICE regimen; 3) pembrolizumab + gemcitabine, vinorelbine, and pegylated liposomal doxorubicin hydrochloride. Patients achieving CR or partial response (PR) with third-line treatment then undergo ASCT.
Patients in all parts undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan, as well as a biopsy during screening, positron emission tomography (PET) and computed tomography (CT) during screening and on study, and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for up to 2 years after ACT (Part 1 and Arm I) and last dose of pembrolizumab (Part 2 and Arm II) and every 6 months for 2 years and every year for 5 years after last dose of pembrolizumab (Part 2 and Arm II).
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorAlison J. Moskowitz
- Primary ID18-160
- Secondary IDsNCI-2018-01802
- ClinicalTrials.gov IDNCT03618550