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.
- Relapse or refractory disease following 1 or 2 lines of curative-intent chemo-immunotherapy (not including 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
- 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
- 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 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 pneumonitis related to PD-1 blockade that required steroids.
- 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.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03618550.
Locations matching your search criteria
United States
California
Palo Alto
Florida
Miami
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
Pennsylvania
Philadelphia
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 after initiation of pembrolizumab (pembro)-GVD. (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. Assess time-to-event outcomes for sub-cohorts. (Part 3)
XI. Document any non-protocol 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. Estimate time-to-event outcomes. (Part 3 exploratory cohort)
VI. Describe lines of treatment. (Part 3 exploratory cohort)
VII. 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)
VIII. Assess association between pre-transplant tumor-specific cell-free DNA and post-transplant outcomes. (Part 3)
IX. 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 day 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 who do not achieve a complete response (CR) after 2 cycles receive an additional 2 cycles, before undergoing ASCT. Patients undergo stem cell mobilization and collection as per standard institutional guidelines after 2-4 cycles of pembrolizumab-GVD. Patients then undergo ASCT. Patients with stem cell mobilization failure are eligible for ASCT on study if bone marrow harvest is successful. Radiation-naive patients with early stage, nodal-based disease may receive involved-site radiation therapy (ISRT) prior to ASCT.
PART 2 (EXPANSION COHORT): Patients receive pembrolizumab IV on day 1, gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin hydrochloride IV on day 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 are assigned to 1 of 3 cohorts.
COHORT 3A: Patients receive pembrolizumab IV on day 1, gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin hydrochloride IV on day 1 and day 8, and pegfilgrastim SC on day 9. Treatment repeats every 21 days for a minimum of 2 cycles (up to 4 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo stem cell mobilization and collection as per standard institutional guidelines after 2-4 cycles of pembrolizumab-GVD. Patients then undergo ASCT. Patients with stem cell mobilization failure are eligible for ASCT on study if bone marrow harvest is successful. Radiation-naive patients with early stage, nodal-based disease may receive ISRT prior to ASCT.
COHORT 3B: Patients receive pembrolizumab IV on day 1, gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin hydrochloride IV on day 1 and day 8, and pegfilgrastim SC on day 9 and radiation therapy. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning 3-5 weeks after cycle 4 of pembro-GVD, patients receive an additional 13 cycles of maintenance pembrolizumab. Patients may also undergo ISRT 6 weeks after completion of pembro-GVD and concurrently with pembrolizumab maintenance. Patients who develop disease progression during or after maintenance pembrolizumab proceed to third-line therapy comprising carboplatin, etoposide and ifosfamide (ICE), brentuximab vedotin (BV)-ICE, BV-bendamustine, or pembro-GVD (for patients in remission at least 1 year from last cycle of pembro-GVD). Patients with CR or partial response (PR) to third-line therapy proceed to high dose therapy (HDT)/ASCT. Patients undergo stem cell mobilization and collection as per standard institutional guidelines. Patients with stem cell mobilization failure are eligible for ASCT on study if bone marrow harvest is successful.
EXPLORATORY COHORT: Patients receive pembrolizumab IV on day 1 of each cycle. Treatment repeats every 21 days for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo ISRT 6 weeks after completion of pembro-GVD and concurrently with pembrolizumab maintenance.
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 2 years after the last dose of pembrolizumab, every 6 months for 2 years and every 1 year for 5 years following the last pembrolizumab dose.
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