Title A Phase Ib study of the safety and pharmacokinetics of atezolizumab (anti-pd-l1 antibody) alone or in combination with an immunomodulatory drug and/or daratumumab in patients with multiple myeloma (relapsed/refractory and post-autologous stem cell transplantation)
IRB ROCH 1A18
Hospital Main Campus
Phase Phase 1
Disease Multiple Myeloma
Drug Atezolizumab , Daratumumab
This study will evaluate the safety, efficacy, and pharmacokinetics of atezolizumab alone and in combination with various immunomodulatory agents (i.e., IMiDs, daratumumab) in patients with relapsed/refractory multiple myeloma or patients with myeloma who have measureable disease post-ASCT, but without overt, clinical progression. Specific objectives and corresponding endpoints for the study are outlined in Table 1.
- Age ≥ 18 years
- Given voluntary written informed consent before performance of any study-related procedures not part of normal medical care
- Previously diagnosed with MM based on standard criteria
- Patients enrolled in Cohorts A, B, C, D1, and E must have received at least one, but not more than three, prior lines of therapy. For the purposes of this study, induction chemotherapy, consolidation with ASCT, maintenance therapy with lenalidomide alone at a dose of no more than 15 mg daily will be considered collectively as one line of therapy. ASCT more than 6 months after completion of induction chemotherapy or undertaken for progression of disease (i.e., salvage therapy) will be considered a separate line of therapy. Post-ASCT with lenalidomide at a dose greater than 15 mg daily or in combination with another agent (e.g., dexamethasone) will be considered a separate line of therapy (see Appendix 4 for more detailed guidance on determination of prior lines of therapy).
- Patients enrolled in Cohort D2 must have received two but not more than three prior lines of therapy that must have included a proteasome inhibitor and an IMiD (alone or in combination) and be refractory to the last line of treatment.
- Patients enrolled in Cohort D3 must have received two or more lines of prior therapy, be refractory to both a proteasome inhibitor and an IMiD, and have progressed on treatment (as defined by IMWG criteria) with an anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab, MOR202) either as a single agent or as a combination. The most recent regimen must have contained an anti-CD38 monoclonal antibody and patients must have achieved at least a minimal response (per IMWG criteria) with anti-CD38-containing therapy.
- Patients enrolled in Cohort F must have received four or more lines of prior therapy (see Appendix 4 for more detailed guidance on determination of prior lines of therapy) and be refractory to the last line of treatment.
- Relapsed disease, defined as previously treated myeloma that progresses and requires the initiation of salvage therapy, but does not meet criteria for "primary refractory disease" or "relapsed and refractory" disease (Rajkumar et al. 2011) or
- Refractory disease, defined as disease that is non-responsive to salvage therapy or progresses within 60 days following completion of the most recent therapy with achievement of at least a minimal response (MR) or better before disease progression
- Willing and able to undergo BM aspiration and biopsy tissue sample collection during screening and while in the study. Pre-treatment-evaluable tissue is required for study entry.
- Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2 (see Appendix 5)
- Measurable disease defined as at least one of the following:
- Serum M protein ≥ 0.5 g/dL (≥ 5 g/L)
- Urine M protein ≥ 200 mg/24 hr
- Serum free light chains (sFLC) assay: Involved sFLCs ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal sFLC ratio (< 0.26 or > 1.65)
- Baseline cardiac left ventricular ejection fraction is ≥ 40% by either echocardiography or multi-gated angiography scan (MUGA)
- Negative serum or urine pregnancy test result for women of childbearing potential (see Section 4.5.6)
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab or 90 days after the last dose of daratumumab, or 30 days after the last dose of lenalidomide or pomalidomide, whichever is longer A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 90 days after the last dose of lenalidomide or pomalidomide. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- No contraindications to atezolizumab.
- History of other malignancy within 2 years prior to screening, except those with negligible risk of metastasis or death (e.g., 5-year OS ≥ 90%), such as ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer (Gleason score ≤ 7) not requiring treatment or appropriately treated Stage I uterine cancer
- Prior therapy with atezolizumab or other immunotherapeutics, including CD137 agonists, anti-PD-1, anti-CTLA-4, and anti-PD-L1 therapeutic antibodies
- Uncontrolled cancer pain. Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy (e.g., bony lesions or plasmacytoma) should be treated prior to enrollment.
- Treatment with any investigational drug within 30 days or 5 half-lives of the investigational drug, whichever is longer
- History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins or a known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the atezolizumab or daratumumab formulations
- Prior diagnoses of autoimmune disease including but not limited to uncontrolled autoimmune thyroid disease or Type 1 diabetes, systemic lupus erythematosis, Sjogren's syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, idiopathic pulmonary fibrosis (IPF, including bronchiolitis obliterans organizing pneumonia), and inflammatory bowel disease, will be excluded from study participation. Patients with autoimmune thyroid disease and Type 1 diabetes that is well controlled on a stable medication regimen may be eligible for the study (see Appendix 8).
- Prior systemic, anti-myeloma therapy within 14 days of Cycle 1, Day 1
- Primary refractory MM defined as disease that is non-responsive in patients who have never achieved a minimal response or better with any therapy
- Prior treatment with chimeric antigen receptor (CAR) T cells or other forms of adoptive cellular therapy, with the exception of autologous stem cell transplantation
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
- Plasma cell leukemia (> 2.0 x 109/L circulating plasma cells by standard differential)
- Any Grade > 1 (according to the NCI CTCAE v.4.0) adverse reaction unresolved from previous treatments or not readily managed and controlled with supportive care. The presence of alopecia or peripheral neuropathy ≤ Grade 2 without pain is allowed.
- Previous allogeneic stem cell transplant or solid organ transplant
- Immunosuppressive therapy (not limited to but including azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate, and anti- tumor necrosis factor [TNF] agents) within 6 weeks of Cycle 1, Day 1
- Daily requirement for corticosteroids (> 10 mg prednisone daily or equivalent) (except for inhalation corticosteroids) within 2 weeks prior to Cycle 1, Day 1
- Positive HIV test at screening
- Active hepatitis B virus (HBV) (chronic or acute, defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per local guidelines.
- Active hepatitis C virus (HCV) Patients who have a positive HCV antibody test are eligible for the study if a polymerase chain reaction assay is negative for HCV RNA.
- Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4, congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication)
- LVEF < 40%
- Uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension, IPF) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study
- History of pneumonitis
- Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant or breastfeeding females
- Receipt of a live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study Influenza vaccination should be given during influenza season only (approximately October through May in the Northern Hemisphere and approximately April through September in the Southern Hemisphere). Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to initiation of study treatment, during treatment, or within 5 months following the last dose of atezolizumab (for patients randomized to atezolizumab).
- Serious infection requiring oral or IV antibiotics within 14 days prior to enrollment (discussion with the Medical Monitor is encouraged in cases where further clarification may be required) Patients on prophylactic antibiotics, antifungals and antivirals in the absence of documented infection are eligible
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's or Medical Monitor's judgment, precludes the patient's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results