FDA placed on partial hold due to additional data

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.

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.

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.

All enrolled subjects.

All adverse events (AEs) occurring between the signing of informed consent and the off-study date were documented, regardless of the causal relationship to study drug. AEs occurring after the first dose of study drug were considered treatment emergent (i.e., TEAEs). The AE reporting period for this study was up to 14 months.

AE documentation included onset/resolution dates, severity using the NCI CTCAE (version 4.03), seriousness, relationship to study drug, study drug action taken, treatment, and outcome. In summaries, treatment-related AEs included those with a "possible", "probable", or "definite" relationship to the indicated study drug; preferred terms were counted only once per subject at the maximum reported grade.

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.