A Study to Determine the Efficacy of the Combination of Daratumumab (DARA) Plus Durvalumab (DURVA) (D2) in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: DARATUMUMAB; DURVALUMAB
Intervention description: DARATUMUMAB; DURVALUMAB
Intervention MeSH terms: Durvalumab; Daratumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Multiple Myeloma; Daratumumab; Durvalumab; Relapsed and Refractory Multiple Myeloma

Summary:

      This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the
      combination regimen of daratumumab plus durvalumab (D2). The study will consist of 2 parts;
      Part 1 has a 2-stage design while Part 2 consists of an expansion phase. Subjects will
      receive intravenous (IV) DARA at 16 mg/kg on the same dosing schedule (weekly [QW], every 2
      weeks [Q2W] or every 4 weeks [Q4W] of each 28-day cycle) received on their last prior therapy
      containing DARA. The dosing schedule for DARA may be adjusted during the course of the study
      as outlined in the protocol. Subjects will also receive IV DURVA at 1500 mg on Day 2 (Cycle
      1) and on Day 1 (Cycles ≥ 2) of each 28-day treatment cycle.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects must satisfy the following criteria to be enrolled in the study:

          1. Subject received at least 3 prior anti-myeloma regimens including a proteasome
             inhibitor (PI) and an immunomodulatory agent or is double-refractory to a PI and an
             immunomodulatory agent.

               -  Induction, bone marrow transplant with or without maintenance therapy is
                  considered one regimen.

               -  Refractory is defined as disease that is nonresponsive on therapy, or progresses
                  within 60 days of last therapy. Nonresponsive disease is defined as either
                  failure to achieve minimal response or development of progressive disease while
                  on therapy.

               -  For subjects who received more than 1 regimen containing a PI their disease must
                  be refractory to the most recent PI containing regimen.

               -  For subjects who received more than 1 regimen containing a immunomodulatory agent
                  their disease must be refractory to the most recent immunomodulatory agent
                  containing regimen.

          2. All subjects must have failed Daratumumab (DARA) either as a single agent or in
             combination on last Multiple myeloma (MM) therapy. Failure is defined as disease
             progression(PD) on DARA either as a single agent or in combination.

          3. Subject has measurable disease defined as:

               1. M-protein (serum protein electrophoresis (sPEP) or urine protein electrophoresis
                  (uPEP): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours) and/or

               2. Light chain MM without measurable disease in the serum or the urine: serum
                  immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa
                  lambda free light chain ratio

          4. Subject achieved a response (minimal response [MR] or better) to at least 1 prior
             treatment regimen.

          5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 2
             or less.

          6. Subject's toxicities resulting from previous therapy (including peripheral neuropathy)
             have resolved or stabilized to ≤ Grade 1.

          7. Subject is at least 18 years of age the time of signing the informed consent form
             (ICF).

          8. Subject must understand and voluntarily sign an ICF prior to any study-related
             assessments/procedures being conducted.

          9. Subject is willing and able to adhere to the study visit schedule and other protocol
             requirements.

         10. Females of childbearing potential (FCBP) must:

             a. Have 2 negative pregnancy tests as verified by the investigator prior to starting
             study treatment. This applies even if the subject practices true abstinence from
             heterosexual contact.

             i. Negative serum pregnancy test at screening ii. Negative serum or urine pregnancy
             test (investigator's discretion) within 72 hours prior to starting study treatment
             (Cycle 1, Day 1), and before beginning each subsequent cycle of treatment, and after
             end of study treatment.

             b. Either practice true abstinence from heterosexual contact (which must be reviewed
             on a monthly basis and source documented) or agree to use, and be able to comply with,
             effective contraception without interruption (eg, oral, inject able, or implantable
             hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive
             with spermicide; true abstinence; or vasectomized partner), 28 days prior to starting
             study treatment, during the study therapy (including dose interruptions), and for at
             least 90 days after discontinuation of study treatment.

             c. Agree to abstain from breastfeeding during study participation and for at least 90
             days after the last dose of Daratumumab (DARA) or Durvalumab (DURVA), whichever is
             later.

             d. Refrain from egg cell donation for at least 90 days after the final dose of DURVA
             or DARA, whichever is later.

         11. Male subjects must:

               1. Either 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 female of
                  childbearing potential 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 donation for at least 90 days after the final dose of DURVA or
                  DARA, whichever is later.

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrollment:

          1. Subject has had prior exposure to anti-CTLA-4, anti-PD-1 (Programmed cell death-1),
             anti-PD-L1 (Programmed death-ligand 1) Monoclonal antibody (mAbs), or cancer vaccines

          2. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks
             before the date of randomization.

          3. History of organ or allogeneic stem cell transplantation

          4. Subject received any of the following within the last 14 days of initiating study
             treatment:

               1. Plasmapheresis

               2. Major surgery (as defined by the investigator)

               3. Radiation therapy other than local therapy for myeloma associated bone lesions

               4. Use of any systemic anti-myeloma drug therapy (except for DARA either alone or in
                  combination with other agents given with it)

          5. Subject received prior treatment with a monoclonal antibody within 5 half-lives of
             initiating study treatment, other than DARA.

          6. Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for
             cancer treatment. Note: Concurrent use of hormones for noncancer-related conditions
             (eg, insulin for diabetes and hormone replacement therapy) is acceptable.

          7. Subject has any of the following laboratory abnormalities:

               1. Absolute neutrophil count (ANC) < 1,000/µL

               2. Platelet count: < 75,000/µL (it is not permissible to transfuse a subject to
                  reach this level)

               3. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject
                  to reach this level)

               4. Creatinine clearance (CrCl) < 45 mL/min (calculated using the Cockcroft-Gault
                  formula or directly calculated from the 24-hour urine collection method)

               5. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)

               6. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 ×
                  upper limit of normal (ULN)

               7. Serum total bilirubin > 1.5 × upper limit of normal (ULN) or > 3.0 mg/dL for
                  subjects with documented Gilbert's syndrome

          8. Subject has clinical evidence of central nervous system (CNS) or pulmonary
             leukostasis, disseminated intravascular coagulation, or CNS MM

          9. Subject has known chronic obstructive pulmonary disease (COPD) with a forced
             expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that forced
             expiratory testing (FEV1) is required for subjects suspected of having COPD and
             subjects must be excluded if FEV1 is < 50% of predicted normal.

         10. Subject has known moderate or severe persistent asthma within the past 2 years or
             uncontrolled asthma of any classification. Note that subjects who currently have
             controlled intermittent asthma or controlled mild persistent asthma are allowed to
             participate in the study.

         11. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome
             (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes),
             or amyloidosis

         12. Subject has nonsecretory MM

         13. Subject has known allergy or hypersensitivity to study drug formulations

         14. Subject has active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis, celiac
             disease, irritable bowel disease, or other serious gastrointestinal chronic conditions
             associated with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia
             gravis; Graves' disease; rheumatoid arthritis, hypophysitis, uveitis, etc) 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's disease) stable on
                  hormone replacement.

               3. Psoriasis not requiring systemic treatment.

         15. Subject has history of primary immunodeficiency

         16. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active
             hepatitis B or active hepatitis A or C.

         17. Subject has received live, attenuated vaccine within 30 days prior to the first dose
             of DURVA (NOTE: Subjects, if enrolled, should not receive live vaccine during the
             study and through 30 days after the last dose of DURVA)

         18. Subject is currently using or has used immunosuppressive medication within 14 days
             prior to the first study dose of study treatment. The following are exceptions to this
             criterion:

               1. Intranasal, topical, inhaled, 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, infusion-related
                  reactions, computed tomography [CT] scan premedication).

         19. Subject has any one of the following:

               1. Clinically significant abnormal Electrocardiogram (ECG) finding at screening

               2. Congestive heart failure (New York Heart Association Class III or IV)

               3. Myocardial infarction within 12 months prior to starting study treatment

               4. Unstable or poorly controlled angina pectoris, including Prinzmetal variant
                  angina pectoris

         20. Subject has 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 noninvasive
             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

         21. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to
             become pregnant during the participation in the study.

         22. Subject has any significant medical condition, laboratory abnormality, or psychiatric
             illness that would prevent the subject from participating in the study

         23. Subject has any condition including the presence of laboratory abnormalities, which
             places the subject at unacceptable risk if he/she were to participate in the study

         24. Subject has any condition that confounds the ability to interpret data from the study