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Trial record 1 of 1 for:    MEDI4736-MM-002
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A Study of Durvalumab in Combination With Lenalidomide With and Without Dexamethasone in Subjects With Newly Diagnosed Multiple Myeloma

This study is currently recruiting participants.
See Contacts and Locations
Verified July 2017 by Celgene
Sponsor:
Information provided by (Responsible Party):
Celgene
ClinicalTrials.gov Identifier:
NCT02685826
First received: February 16, 2016
Last updated: July 21, 2017
Last verified: July 2017
  Purpose

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 subjects 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.


Condition Intervention Phase
Multiple Myeloma Drug: Durvalumab Drug: Lenalidomide Drug: Dexamethasone Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Multicenter, Open-label Study to Determine the Recommended Dose and Regimen of Durvalumab (MEDI4736) (DUR) in Combination With Lenalidomide (LEN) With and Without Low-dose Dexamethasone (Dex) in Subjects With Newly Diagnosed Multiple Myeloma (NDMM)

Resource links provided by NLM:


Further study details as provided by Celgene:

Primary Outcome Measures:
  • Dose-limiting toxicities (DLTs) [ Time Frame: Approximately 1 month ]
    Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in the dose-finding portion of the study.


Secondary Outcome Measures:
  • Adverse Events (AEs) [ Time Frame: Up to approximately 2 year ]
    Number of participants with adverse events

  • Overall Response Rate [ Time Frame: up to approximately 2 year ]
    Is defined as tumor response, based on the investigator assessments according to the International Myeloma Working Group (IMWG) Uniform Response Criteria

  • Response Improvement Rate (RIR) [ Time Frame: Up to approximately 2 years ]
    Is defined as response improved from the assessment at the Cycle 1 Day1

  • Time to Response (TTR) [ Time Frame: up to approximately 2 year ]
    Is defined as time from Cycle 1 Day1 to the first documentation of response

  • Duration of Response (DOR) [ Time Frame: up to approximately 2 year ]
    Time from the first response to the first documentation of disease progression or death, whichever is earlier, based on the investigator assessments according to the IMWG Uniform Response Criteria

  • Pharmacokinetic- Cmax [ Time Frame: approximately 1 year ]
    Maximum observed concentration

  • Pharmacokinetic- AUC [ Time Frame: approximately 1 year ]
    Area under the concentration-time curve

  • Pharmacokinetic- Tmax [ Time Frame: approximately 1 year ]
    Time to maximum concentration

  • Pharmacokinetic- t1/2 [ Time Frame: approximately 1 year ]
    Terminal elimination half-life

  • Pharmacokinetic- CL/F [ Time Frame: approximately 1 year ]
    Apparent total body clearance

  • Pharmacokinetic- Vz/F [ Time Frame: approximately 1 year ]
    Volume of distribution

  • Progression-Free Survival (PFS) [ Time Frame: Approximately 8 years ]
    Time from cycle 1 day 1 (C1D1) to the first documentation of disease progression or death from any cause during study, whichever occurs earlier

  • Overall Survival(OS) [ Time Frame: Approximately 8 years ]
    Time from cycle 1 day 1 to death due to any cause


Estimated Enrollment: 120
Actual Study Start Date: April 25, 2016
Estimated Study Completion Date: August 8, 2024
Estimated Primary Completion Date: April 1, 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Durvalumab 1500mg, Lenalidomide 25mg, Dexamethasone 40mg

Durva+Len+Dex Cohort A for high risk transplant non-eligible NDMM subjects

  • Intravenous (IV) durvalumab (Durva) at 1500 mg on Day 1 of a 28-day cycle,
  • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle
  • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15,and 22 of each 28-day cycle.
Drug: Durvalumab Drug: Lenalidomide Drug: Dexamethasone
Experimental: Durva 1500mg, Len 25mg, Dex 40mg- up to 12 cycles

Cohort B for ≥65 years old TNE NDMM non high risk subjects

  • Intravenous durvalumab at 1500 mg on Day 1 of a 28-day cycle,
  • Oral LEN 25 mg/day (adjust per the CrCl value) on Days 1 to 21 of each 28-day treatment cycle,
  • Oral dex 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15,and 22 of each 28-day cycle (for up to 12 cycles
Drug: Durvalumab Drug: Lenalidomide Drug: Dexamethasone
Experimental: Durvalumab 1500mg, Lenalidomide 10mg

Cohort C for high risk post-transplant NDMM subjects

  • Intravenous durvalumab at 1500 mg on Day 1 of a 28-day cycle
  • Oral Lenalidomide (LEN) 10 mg/day on Days 1 to 21 of each 28-day treatment cycle
Drug: Durvalumab Drug: Lenalidomide

Detailed Description:

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 on high risk Transplant non-eligible (TNE) Newly diagnosed multiple myeloma (NDMM) subjects;
  • Cohort B: durvalumab + LEN +dex (Dex for up to 12 cycles) on ≥ 65 years old TNE NDMM subjects who are not high risk;
  • Cohort C: durvalumab + LEN as maintenance on post-transplant high risk NDMM subjects; 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 CrCl) value on Days 1 to 21 of each 28-day treatment cycle for subjects on Cohort A and B. The dose of LEN will be 10 mg on Days 1 to 21 of each 28-day treatment cycle for subjects on Cohort C.

The dose of dex will be 40 mg/day (for subjects ≤ 75 years old) or 20 mg/day (for subjects > 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 subjects 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 subjects experience a DLT within the first cycle, then the doseexpansion phase may be initiated with durvalumab 1500 mg as the recommended dose (RD);
  • If 2 or more of the 6 initial subjects 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 PK/Pd of the initial 6 subjects by the 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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:
  • 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 PET-CT
  • 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:

  • IgG MM: Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dl or urine Mprotein level ≥ 200 mg/24 hours- IgA MM: Serum M-protein level ≥ 0.5 g/dl or urine M-protein level ≥ 200 mg/24 hours
  • 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
  • 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 (FCBP1) must:

    1. 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 abstinence2 from heterosexual contact.
    2. 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.
    3. Refrain from egg cell and blood donation for 90 days after the final dose of durvalumab.

      7. Male subjects must :

    1. Practice true abstinence2 (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.
    2. 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:
    1. 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
    2. ISS Stage III; or
    3. Serum LDH > 2 x 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 x 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02685826

Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

  Show 32 Study Locations
Sponsors and Collaborators
Celgene
Investigators
Study Director: Annette Ervin-Haynes, MPA Celgene
  More Information

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02685826     History of Changes
Other Study ID Numbers: MEDI4736-MM-002
Study First Received: February 16, 2016
Last Updated: July 21, 2017

Keywords provided by Celgene:
Open-label
Phase 1/2
Durvalumab
MEDI4736
Lenalidomide (Len)
Dexamethasone (dex)
Multiple Myeloma
Newly-Diagnosed (NDMM)
Transplant Non-eligible (TNE)
PD-L1

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Lenalidomide
Thalidomide
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on August 23, 2017