Phase 1 Study of Tremelimumab, Durvalumab, High-dose Chemotherapy, + Autologous Stem Cell Transplant

NCT02716805 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: LUD2014-010
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 2

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.

Conditions

Multiple Myeloma

Keywords

autologous stem cell transplant; HDT/ASCT; CTLA-4; PD-L1; peripheral blood mononuclear cells; PBMC; ASCT

Outcome Measures

Primary Outcomes (1)

• Number of Subjects With Treatment-emergent Adverse Events

  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.

  up to 14 months

Secondary Outcomes (1)

• Number of Subjects With Best Response According to International Myeloma Working Group (IMWG) Consensus Criteria

  Up to 14 months

Study Arms (4)

Cohort 1

EXPERIMENTAL

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.

Drug: Tremelimumab; Drug: Durvalumab; Biological: Prevnar-13; Drug: Melphalan

Cohort 2

EXPERIMENTAL

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.

Drug: Tremelimumab; Drug: Durvalumab; Biological: Prevnar-13; Drug: Melphalan

Cohort 3

EXPERIMENTAL

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.

Drug: Tremelimumab; Drug: Durvalumab; Biological: Prevnar-13; Drug: Melphalan

Cohort 4

EXPERIMENTAL

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.

Drug: Tremelimumab; Drug: Durvalumab; Biological: Prevnar-13; Drug: Melphalan

Interventions

Tremelimumab DRUG

Tremelimumab was administered as an intravenous (IV) infusion over 60 ± 5 minutes at a fixed dose of 75 mg, regardless of weight.

Also known as: MEDI1123

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Durvalumab DRUG

Durvalumab was administered as an IV infusion over 60 ± 5 minutes at a fixed dose of 1500 mg for subjects weighing \> 30 kg. If a subject's body weight dropped to ≤ 30 kg on study, the subject was dosed at 600 mg for as long as the body weight remained ≤ 30 kg. When applicable, the durvalumab infusion was to start at least 60 minutes after the end of the tremelimumab infusion.

Also known as: MEDI4736

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Prevnar-13 BIOLOGICAL

Prevnar-13 was administered as an intramuscular injection. The Prevnar-13 dose and the tremelimumab dose were to be separated by a minimum of 48 hours.

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Melphalan DRUG

Melphalan was administered as an IV infusion according to institutional standard of care and local prescribing information.

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• Able and willing to provide consent for required bone marrow biopsies.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Anticipated lifespan greater than 3 months.
• Adequate organ function, as defined below:
• Total bilirubin within normal ranges unless associated with hepatobiliary metastases or Gilbert syndrome, then total bilirubin ≤ 2 x upper limit of normal (ULN)

You may not qualify if:

• 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.
• Other active serious illnesses (e.g., serious infections requiring antibiotics).
• Prior treatment in any other clinical trial involving another investigational agent within 4 weeks prior to Day -31 of the study; resolution of respective adverse event (AE) to Grade 1 or lower should have occurred.
• Major surgical procedure (as defined by the Investigator) within 30 days prior to Day -31 or still recovering from prior surgery.
• Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
• Lack of availability for immunological and clinical follow-up assessments.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• MedImmune LLC: collaborator
• Cancer Research Institute, New York City: collaborator
• Multiple Myeloma Research Foundation: collaborator

Study Sites (2)

Research Facility

New York, New York, 10029, United States

Location

Research Facility

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Multiple Myeloma; Diabetes Mellitus, Insulin-Dependent, 12

Interventions

tremelimumab; durvalumab; Melphalan

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Limitations and Caveats

Early termination due to safety signals in other studies investigating combination regimens comprising similar drugs. Because only 6 subjects were enrolled, no final statistical analysis plan was issued and no formal data analyses were performed.

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• Alexander M. Lesokhin, MD

  Memorial Sloan Kettering Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2016
• First Posted: March 23, 2016
• Study Start: December 13, 2016
• Primary Completion: February 16, 2018
• Study Completion: February 16, 2018
• Last Updated: October 12, 2022
• Results First Posted: March 26, 2019

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)