Phase 1 Study of Tremelimumab, Durvalumab, High-dose Chemotherapy, + Autologous Stem Cell Transplant
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma
Intervention: Tremelimumab; Durvalumab; Prevnar-13; Melphalan
Intervention description: Tremelimumab was administered as an intravenous (IV) infusion over 60 ± 5 minutes at a fixed dose of 75 mg, regardless of weight.; 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.; 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.; Melphalan was administered as an IV infusion according to institutional standard of care and local prescribing information.
Intervention MeSH terms: Melphalan; Durvalumab; Tremelimumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: autologous stem cell transplant; HDT/ASCT; CTLA-4; PD-L1; peripheral blood mononuclear cells; PBMC; ASCT

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically confirmed multiple myeloma.

          2. 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

          3. Available CD34+ stem cells (≥ 2 x 10^6/kg).

          4. Eligible for autologous stem cell transplantation.

          5. 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).

          6. Able and willing to provide consent for required bone marrow biopsies.

          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          8. Anticipated lifespan greater than 3 months.

          9. 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)

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN

               -  Creatinine ≤ 2.0 mg/dL

               -  Carbon monoxide diffusing capacity (DLCO) ≥ 50%

         10. Had been informed of other treatment options.

         11. Age ≥ 18 years.

         12. Able and willing to give valid written informed consent.

         13. Body weight > 30 kg.

        Exclusion Criteria:

          1. 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.

          2. History of severe allergic reactions to any unknown allergens or any components of the
             study drugs.

          3. Active or prior autoimmune disease except for autoimmune thyroiditis, vitiligo, or
             psoriasis not requiring systemic therapy.

          4. Prior allogeneic transplantation.

          5. Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior
             corticosteroid-refractory irAE.

          6. Known active or chronic viral hepatitis or history of any type of hepatitis within the
             last 6 months.

          7. History of sarcoidosis syndrome.

          8. 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.

          9. Metastatic disease to the central nervous system for which other therapeutic options,
             including radiotherapy, were available.

         10. Known immunodeficiency or active human immunodeficiency virus.

         11. Other active serious illnesses (e.g., serious infections requiring antibiotics).

         12. 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.

         13. Major surgical procedure (as defined by the Investigator) within 30 days prior to Day
             -31 or still recovering from prior surgery.

         14. Mental impairment that may have compromised the ability to give informed consent and
             comply with the requirements of the study.

         15. Lack of availability for immunological and clinical follow-up assessments.

         16. Women who were breastfeeding or pregnant as evidenced by positive serum pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]).

         17. Female subjects of childbearing potential who were sexually active with a
             nonsterilized male partner must have used at least one highly effective method of
             contraception from the time of screening, and must have agreed to continue using such
             precautions for 90 days after the last dose of durvalumab or for 6 months after the
             last dose of tremelimumab (whichever was longer). Non-sterilized male partners of a
             female subject must have used male condoms plus spermicide throughout this period.
             Cessation of birth control after this point should have been discussed with a
             responsible physician. Not engaging in sexual activity for the total duration of the
             trial and the drug washout period was an acceptable practice; however, periodic
             abstinence, the rhythm method, and the withdrawal method were not acceptable methods
             of birth control.

             Female subjects should have refrained from breastfeeding throughout the period
             described above.

             Females of childbearing potential were defined as those who were not surgically
             sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
             hysterectomy) or postmenopausal.

             Females were considered post-menopausal if they had been amenorrheic for 12 months
             without an alternative medical cause. The following age-specific requirements applied:

               -  Females < 50 years of age were considered post-menopausal if they had been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they had luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Females ≥ 50 years of age were considered post-menopausal if they had been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

             Women of childbearing potential must have had a negative serum β-HCG pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of HCG) conducted during screening
             and a negative urine β-HCG pregnancy test conducted prior to study drug administration
             on Day -31. Ongoing serum pregnancy tests were conducted according to the study
             protocol.

             Nonsterilized male subjects who were sexually active with a female partner of
             childbearing potential must have used male condoms plus spermicide from screening
             through 90 days after last dose of durvalumab or through 6 months after the last dose
             of tremelimumab (whichever was longer). Female partners (of childbearing potential) of
             a male subject must have used a highly effective method of contraception throughout
             the period described above. Cessation of birth control after this point should have
             been discussed with a responsible physician. Not engaging in sexual activity for the
             total duration of the trial and the drug washout period was an acceptable practice;
             however, periodic abstinence, the rhythm method, and the withdrawal method were not
             acceptable methods of contraception.

             Male subjects should have refrained from sperm donation throughout this period. A
             highly effective method of contraception was defined as one that resulted in a low
             failure rate (i.e., less than 1% per year) when used consistently and correctly. Note
             that some contraception methods were not considered highly effective (e.g., male or
             female condom with or without spermicide; female cap, diaphragm, or sponge with or
             without spermicide; non-copper containing intrauterine device; progestogen-only oral
             hormonal contraceptive pills where inhibition of ovulation is not the primary mode of
             action [excluding Cerazette/desogestrel which was considered highly effective]; and
             triphasic combined oral contraceptive pills).

         18. Any condition that, in the clinical judgment of the treating physician, was likely to
             prevent the subject from complying with any aspect of the protocol or that may have
             put the subject at unacceptable risk.

         19. Subjects must not have donated blood while on study and for at least 90 days following
             the last durvalumab treatment or for 6 months following the last tremelimumab
             treatment, whichever was longer.