A Study of Durvalumab in Combination With Lenalidomide With and Without Dexamethasone in Adults With Newly Diagnosed Multiple Myeloma

This is a multicenter, open-label, Phase 1/2 study to determine the recommended dose and regimen of durvalumab in combination with lenalidomide (LEN) with and without dexamethasone (dex) in adults with newly diagnosed multiple myeloma (NDMM).

The study will consist of a dose-finding phase as well as a parallel dose-expansion phase to determine the optimal regimen.

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The study was placed on full clinical hold by the United States (US) Food and Drug Administration (FDA) on 05 Sep 2017. The decision by the FDA was based on data from non-Celgene-sponsored studies related to risks of anti-programmed cell death 1 (PD-1), pembrolizumab, in combination with immunomodulatory agents. As the result, the study was closed for further enrollment, and all subjects were discontinued from all study treatments (durvalumab, lenalidomide and dexamethasone). All subjects are being followed for second primary malignancies (SPMs), every 6 months for 5 years after the last subject has been enrolled as per protocol. After stopping data collection in the clinical database, any SPM events will continue to be recorded in the subject's source documents, and reported to Celgene Drug Safety.

The dose-finding phase will determine recommended dose (RD) for durvalumab in combination with lenalidomide (LEN) with and without dexamethasone (dex) in a 28-day treatment cycle. Three treatment Cohorts (A, B, and C) will be enrolled in parallel:

* Cohort A: durvalumab + LEN + dex in high risk transplant non-eligible (TNE) newly diagnosed multiple myeloma (NDMM) participants;
* Cohort B: durvalumab + LEN + dex (dex for up to 12 cycles) in ≥ 65 years old TNE NDMM participants who are not high risk;
* Cohort C: durvalumab + LEN as maintenance in post-transplant high risk NDMM participants.

Based on experience with durvalumab for other indications, the initial dose of durvalumab will be 1500 mg for each treatment cohort. The dose of durvalumab might be de-escalated to 750 mg level.

The dose of LEN will be 25 mg (adjustable per the creatinine clearance \[CrCl\] value) on Days 1 to 21 of each 28-day treatment cycle for participants in Cohort A and B. The dose of LEN will be 10 mg on Days 1 to 21 of each 28-day treatment cycle for participants in Cohort C.

The dose of dex will be 40 mg/day (for participants ≤ 75 years old) or 20 mg/day (for participants \> 75 years old) on Days 1, 8, 15, and 22 of a 28-day cycle for Cohort A and Cohort B (for up to 12 cycles).

Initially, 6 participants will be enrolled into each cohort and each will receive 1500 mg durvalumab.

The dose-limiting toxicity (DLT) evaluation period will be the first treatment cycle.

* If ≤ 1 of the 6 initial participants experience a DLT within the first cycle, then the dose expansion phase may be initiated with durvalumab 1500 mg as the recommended dose (RD);
* If 2 or more of the 6 initial participants experience a DLT within the first cycle, then the maximum tolerated dose (MTD) has been exceeded and de-escalation to durvalumab 750 mg level after review of safety and pharmacokinetic/pharmacodynamic (PK/Pd) of the initial 6 participants by the Dose Review Team (DRT).

Any of the cohorts may be removed from the study based on emerging PK, Pd, efficacy or safety data.

Dose de-escalation will only occur after review of safety (DLT) and possibly PK/Pd data by the Dose Review Team ( DRT).

Note: In the US, two treatment arms (A and B) will be enrolled in parallel. Cohort C will enroll upon completion of at least 4 cycles of follow-up for safety assessment of Cohorts A and B.

Eligibility Criteria:
Inclusion Criteria:

* Subjects must satisfy the following criteria to be enrolled into the study:

  1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF)
  2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
  3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
  4. Subject must have documented diagnosis with previously untreated (for cohort C, the induction and consolidation treatment along with the first autologous stem cell transplantation (ASCT) are allowed), symptomatic multiple myeloma (MM) as defined by the criteria below:

MM diagnostic criteria (all 3 required);

- Monoclonal protein present in the serum and/or urine

* Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
* Any one or more of the following myeloma defining events:

  1. one or more of the following Myeloma-related organ dysfunction (at least one of the following);
* (C) Calcium elevation (serum calcium \>11.5 mg/dl )(\>2.65 mmol/L)
* (R) Renal insufficiency (serum creatinine \>2 mg/dl)(177 µmol/L or more) or creatinine clearance \< 40 ml/min
* (A) Anemia (hemoglobin \<10 g/dL or \>2 g/dL below the lower limit of laboratory normal)
* (B) Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-computed tomography (PET-CT)

  2. one or more of the following biomarkers of malignancy:
* Clonal bone marrow plasma cell percentage ≥60%
* Abnormal serum free light-chain ratio ≥100 (involved kappa) or \< 0.01 (involved lambda)
* \>1 focal lesions detected by functional imaging including PET/CT and/or whole body magnetic resonance imaging (MRI)

AND have measurable disease by protein electrophoresis analyses as defined by the following:

* Immunoglobulin G (IgG) MM: Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dl or urine Mprotein level ≥ 200 mg/24 hours
* Immunoglobulin A (IgA) MM: Serum M-protein level ≥ 0.5 g/dl or urine M-protein level ≥ 200 mg/24 hours
* Immunoglobulin M (IgM) MM (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours
* Immunoglobulin D (IgD) MM: Serum M-protein level ≥ 0.05 g/dl or urine M-protein level ≥ 200 mg/24 hours
* Light chain MM: Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours

  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

  6. Females of childbearing potential (FCBP) must:

  a. Have two negative pregnancy tests as verified by the investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.

  b. She must either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and be source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study treatment, during the study therapy (including dose interruptions), and for 90 days after discontinuation of study treatment.

  c. Refrain from egg cell and blood donation for 90 days after the final dose of durvalumab.

  7. Male subjects must :

  a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions and for at least 90 days following study treatment discontinuation, even if he has undergone a successful vasectomy.

  b. Refrain from sperm and blood donation for at least 90 days after the final dose of durvalumab.

  8. For Cohort A subject must be transplant non-eligible (TNE) and meet at least one of the following high risk factors:

  a. Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and / or del(17p); and / or 1q amplification; and / or t(14:16); or

  b. International Staging System (ISS) Stage III; or

  c. Serum lactate dehydrogenase (LDH) \> 2\*ULN (upper limit of normal).

  9. For Cohort B subject must be ≥ 65 years of age at the time of signing the informed consent form (ICF) and transplant non-eligible (TNE); excluding the subjects who meet the Cohort A criteria.

  10. For Cohort C subject must be after first autologous stem cell transplantation (ASCT) for NDMM and meet the following criteria:
  1. Have a post-transplant response as Partial response (PR) or better at the time of enrollment to this study;
  2. Have one of the following high risk factors at the time of NDMM diagnosis;
* Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); and / or del(17p); and / or 1q amplification; and / or t(14; 16); or
* ISS stage III; or
* Serum LDH \> 2\*ULN;

  c. Minimal residual disease (MRD) positive (defined as more than 1 malignant cell in 105 cells) measured by ClonoSIGHT™NGS assay of a BMA sample) at the time of enrollment to this study; BMA sample collected at the time of multiple myeloma diagnosis, prior to induction therapy available for central MRD assessment by ClonoSIGHT™NGS assay

Exclusion Criteria:

* The presence of any of the following will exclude a subject from enrollment:

  1. Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid (ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of Cycle 1 Day 1), for Cohort C, the induction and consolidation treatment along with the first Autologous stem cell transplantation (ASCT) are allowed)
  2. Any of the following laboratory abnormalities:

     1. Absolute neutrophil count (ANC) \< 1,000/μL
     2. Untransfused platelet count \< 75,000 cells/μL
     3. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) \> 2.5\*upper limit of normal (ULN)
     4. Serum total bilirubin \> 1.5\*ULN or \> 3.0 mg/dL for subjects with documented Gilbert's syndrome
     5. Corrected serum calcium \>13.5 mg/dL (\> 3.4 mmol/L)
  3. Renal failure requiring hemodialysis or peritoneal dialysis
  4. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, subject with unstable cardiac disease as defined by: cardiac events such as myocardial infarction (MI) within the past 6 months, NYHA (New York Heart Association) heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment
  5. Peripheral neuropathy ≥ Grade 2
  6. Primary AL (immunoglobulin light-chain) amyloidosis and myeloma complicated by amyloidosis
  7. Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following non-invasive malignancies:

     1. Basal cell carcinoma of the skin
     2. Squamous cell carcinoma of the skin
     3. Carcinoma in situ of the cervix
     4. Carcinoma in situ of the breast
     5. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or prostate cancer that is curative
  8. Subjects is positive for human immunodeficiency virus (HIV); chronic or active hepatitis B or active hepatitis A, or C
  9. Subject had prior exposure to immunotherapy, including, but not limited to, other anti- CTLA-4,anti-PD-1, anti-PD-L1 monoclonal antibody or inhibitor, cell-based therapies, or cancer vaccines
  10. Subjects has history of organ or allogeneic stem cell transplantation
  11. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma, or plasma cell leukemia
  12. Known or suspected hypersensitivity to the excipients contained in the formulation of durvalumab, lenalidomide, or dexamethasone
  13. Major surgery (as defined by the investigator) within the 28 days prior to the first dose of study treatment
  14. Received prior treatment (for any reason)with a monoclonal antibody within 5 half-lives of initiating study treatment
  15. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment
  16. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of study treatment. The following are exceptions to this criterion:

      1. Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection);
      2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
      3. Steroids as premedication for hypersensitivity reactions (eg, computed tomography (CT) scan premedication);
  17. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (eg, colitis, Crohn's disease\], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome \[granulomatosis with polyangiitis); myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

      1. Subjects with vitiligo or alopecia;
      2. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; or
      3. Subjects with psoriasis not requiring systemic treatment;
  18. History of primary immunodeficiency
  19. Subject has incidence of gastrointestinal disease that may significantly alter the absorption of LEN
  20. Receipt of live, attenuated vaccine within 30 days prior to the first dose of durvalumab
  21. Unable or unwilling to undergo protocol required thromboembolism prophylaxis(for Cohort C, this will be only for the subjects who have a history of VTE)
  22. Females who are pregnant, nursing or breastfeeding, or intend to become pregnant during the participation to the study
  23. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  24. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
  25. Any condition that confounds the ability to interpret data from the study