A Phase 1 Study to Assess Safety and Tolerability of Tremelimumab and Durvalumab, Administered With High Dose Chemotherapy and Autologous Stem Cell Transplant (HDT/ASCT)
Overview
- Phase
- Phase 1
- Intervention
- Tremelimumab
- Conditions
- Multiple Myeloma
- Sponsor
- Ludwig Institute for Cancer Research
- Enrollment
- 6
- Locations
- 1
- Primary Endpoint
- Number of Subjects With Treatment-emergent Adverse Events
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
This was a Phase 1, open-label, multicenter, study of checkpoint inhibitor therapy (tremelimumab ± durvalumab) prior to and following autologous stem cell transplant (ASCT) and high-dose melphalan in subjects with multiple myeloma who were at a high risk for relapse, were eligible for ASCT, and had available cryopreserved stem cells. Primary study objectives were to determine the safety and tolerability of study treatment. Further objectives were to evaluate the clinical efficacy and biologic activity of the regimen.
Detailed Description
Eligible subjects were to be enrolled sequentially into one of 4 treatment cohorts (beginning with Cohort 1) to receive pretreatment with Prevnar-13 on Day -33 ± 2 days, followed by a single dose of tremelimumab (75 mg) administered either alone (Cohorts 1 and 2) or in combination with a single dose of durvalumab (1500 mg; Cohorts 3 and 4) on Day -31 (approximately 21 days prior to steady-state leukopheresis for the collection of autologous peripheral blood lymphocytes \[PBLs\]). Leukopheresis was performed on Days -10 to -3, followed by high dose therapy (HDT) comprising melphalan (200 mg/m\^2) administered intravenously (IV) on Day -2, and ASCT using previously banked hematopoietic stem cells on Day 0. Autologous PBLs were re-infused into subjects on Day +3 following ASCT, with a single dose of tremelimumab (75 mg) administered on the same day. Following HDT/ASCT, treatment was to resume with tremelimumab (75 mg) administered either alone (Cohorts 1 and 2) or in combination with durvalumab (1500 mg; Cohorts 3 and 4) for the first 2 cycles following HDT/ASCT according to the following schedule. Late post-ASCT treatment: * Cohort 1: tremelimumab (75 mg) administered alone on Day 100 (±10) and 4 weeks later (Cycles 1 and 2) * Cohort 3: tremelimumab (75 mg) + durvalumab (1500 mg) administered on Day 100 (±10) and 4 weeks later (Cycles 1 and 2) Early post-ASCT treatment: * Cohort 2: tremelimumab (75 mg) administered alone on Days 30 through 40 and Day 100 (±10) (Cycles 1 and 2) * Cohort 4: tremelimumab (75 mg) + durvalumab (1500 mg) administered on Days 30 through 40 and Day 100 (±10) (Cycles 1 and 2) For Cycles 3 through 8, durvalumab alone (1500 mg every 4 weeks) was to be administered in all cohorts. Within each cohort, the second subject did not start treatment until the first subject had completed early engraftment (approximately Day 12 to 18 post-ASCT); therefore, the first subject in each cohort received the first dose of tremelimumab ± durvalumab and was observed for toxicity for approximately 7 weeks prior to enrollment of the second subject. Protocol-specified dose-limiting toxicities (DLTs) were assessed from the first dose of study treatment up to and including Cycle 2 dosing (Day 128 for Cohorts 1 and 3 or Day 100 for Cohorts 2 and 4). Subjects were not to be treated in a new cohort until all subjects in the previous cohort had completed the DLT evaluation period and ≤ 1 of 6 subjects had experienced DLT. After enrollment of 6 subjects in Cohort 1, the study was placed on partial clinical hold by the Food and Drug Administration (FDA) due to safety signals observed in other studies investigating pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody, in combination with immunomodulatory agents in subjects with multiple myeloma. As a result, the single subject who was receiving durvalumab during Cycles 3 to 8 discontinued study treatment after Cycle 5; durvalumab was not initiated in the 4 subjects who remained in the study; and no further subjects were enrolled. Upon recommendations from the two Principal Investigators and the study chair, the 4 ongoing subjects, who were in the transplant phase of the study, were permitted to continue post-ASCT tremelimumab treatment after being re-consented under an intermediate expanded access protocol.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed multiple myeloma.
- •Measurable disease either at enrollment, prior to most recent line of salvage therapy, or prior to most recent line of induction therapy. Measurable disease was defined by any of the following:
- •Serum M-spike ≥ 0.5 g/dL
- •Serum free light chain ≥ 10mg/dL
- •Urine monoclonal protein ≥ 200 mg/24 hours
- •Multifocal plasmacytoma
- •≥ 20% bone marrow plasmacytosis
- •Available CD34+ stem cells (≥ 2 x 10\^6/kg).
- •Eligible for autologous stem cell transplantation.
- •Four or less prior lines of systemic therapy for multiple myeloma (induction, first ASCT, consolidation, and maintenance were considered 1 line of therapy unless treatment was modified due to progression of disease as defined by International Myeloma Working Group \[IMWG\] criteria).
Exclusion Criteria
- •Prior exposure to tremelimumab or durvalumab or other anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), anti-PD-1, anti-programmed cell death ligand-1 (PD-L1) antibodies.
- •History of severe allergic reactions to any unknown allergens or any components of the study drugs.
- •Active or prior autoimmune disease except for autoimmune thyroiditis, vitiligo, or psoriasis not requiring systemic therapy.
- •Prior allogeneic transplantation.
- •Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE.
- •Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months.
- •History of sarcoidosis syndrome.
- •Active or history of inflammatory bowel disease (colitis, Crohn's), celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis.
- •Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, were available.
- •Known immunodeficiency or active human immunodeficiency virus.
Arms & Interventions
Cohort 1
Subjects received Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Tremelimumab
Cohort 1
Subjects received Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Durvalumab
Cohort 1
Subjects received Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Prevnar-13
Cohort 1
Subjects received Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Melphalan
Cohort 2
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Tremelimumab
Cohort 2
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Durvalumab
Cohort 2
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Prevnar-13
Cohort 2
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Melphalan
Cohort 3
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Tremelimumab
Cohort 3
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Durvalumab
Cohort 3
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Prevnar-13
Cohort 3
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Late" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Day 100 ± 10 days and Day 128 (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Melphalan
Cohort 4
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Tremelimumab
Cohort 4
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Durvalumab
Cohort 4
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Prevnar-13
Cohort 4
Subjects were to receive Prevnar-13 on Day -33 ± 2 days, tremelimumab (75 mg) + durvalumab (1500 mg) on Day -31, leukopheresis on \~Day -10, melphalan (200 mg/m\^2) on Day -2, ASCT on Day 0, and reinfusion of PBLs and tremelimumab (75 mg) on Day 3. "Early" post-ASCT treatment comprised Prevnar-13 on Days 30 and 60, tremelimumab (75 mg) + durvalumab (1500 mg) on Days 30 through 40 and Day 100 ± 10 days (Cycles 1 and 2), followed by up to 6 cycles of durvalumab (1500 mg) on Day 1 of Cycles 3 through 8.
Intervention: Melphalan
Outcomes
Primary Outcomes
Number of Subjects With Treatment-emergent Adverse Events
Time Frame: up to 14 months
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from the time of enrollment through the end of the study period. DLTs were assessed from the first dose of study drug through the Cycle 2 administration of tremelimumab ± durvalumab post ASCT. DLTs were defined per protocol as lack of neutrophil/platelet engraftment by Day 30 post ASCT; Grade 5 toxicity (treatment-related death); Grade 4 non-hematological toxicity; Grade 3 non-hematological toxicity (with exclusions); isolated Grade 3 electrolyte abnormalities; or immune-related AEs resulting in discontinuation of treatment.
Secondary Outcomes
- Number of Subjects With Best Response According to International Myeloma Working Group (IMWG) Consensus Criteria(Up to 14 months)