IRB Study Number 23-213
Status Recruiting
Institute Taussig Cancer Institute
Description
Dose Escalation (Part A)
Primary Objectives
• To evaluate the safety and tolerability of CB-011 therapy in patients with r/r MM to define the MTD/RDE to determine RP2D
Secondary Objectives
• To characterize the pharmacokinetics and pharmacodynamics of CB-011
• To describe the preliminary antitumor activity of CB-011 in patients with r/r MM
Expansion (Part B)
Primary Objectives
• To evaluate the anti-tumor response of CB-011 in patients with r/r MM
Secondary Objectives
• To evaluate the efficacy of CB-011 in patients with r/r MM
• To further evaluate the safety and tolerability of CB-011 therapy in patients with r/r MM
• To further characterize the PK and pharmacodynamics of CB-011
Inclusion Criteria
- Able to provide informed consent. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the patient’s disease.2.Aged 18 or older at the time of informed consent.3.Documented diagnosis of MM according to International Myeloma Working Group (IMWG)diagnostic criteria.4.Measurable disease at screening as defined by any of the following:
•Serum monoclonal paraprotein (M-protein) level ≥ 1 g/dL or urine M-protein level ≥ 200mg/24 hours; or
• 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. Note: Local laboratory assessments may be used to establish measurable disease at Screening and a local laboratory result must be ≥ 125% of the above requirements. 5. Received at least 3 prior MM treatment lines of therapy which must include a PI, an IMiD, and an anti-CD38 monoclonal antibody as part of a prior line of therapy, either in monotherapy or in combination.
• Refractory MM is defined per IMWG criteria (Appendix 4). Note: induction, consolidation, and maintenance are considered a single line of therapy (with or without autologous stem cell transplant) 6. Undergone at least 2 complete cycles of treatment for each line of therapy, unless progressive disease (PD) was the best response to the line of therapy or the treatment was intolerable. 7. Patients who received prior BCMA-directed therapy are eligible to enroll, provided:
• It was not a CAR-T cell therapy
• last dose was given at least 3 months prior to receiving first dose of CB-011 8. Documented evidence of PD based on Investigator’s determination of response by the IMWG criteria on or within 12 months of their last line of therapy. Confirmation may be from either central or local testing. Also, patients with documented evidence of PD (as above) within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible. 9. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1. 10. Clinical laboratory values meeting the following criteria during the Screening Phase:
• Hematology
o Hemoglobin > 8.0 g/dL (> 5 mmol/L) (without prior red blood cell transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
o Platelets ≥ 50 × 109/L (must be without transfusion support in the 7 days prior to the laboratory test);
o Absolute neutrophil count ≥ 0.75 × 109/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test).
• Chemistry
o AST and ALT ≤ 3.0 × upper limit of normal (ULN);
o Creatinine clearance ≥ 40 mL/min/1.73 m2 based upon Modified Diet in Renal Disease formula calculation or a 24-hour urine collection;
o Total bilirubin ≤ 2.0 × ULN, except in patients with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤ 1.5 × ULN is required); and
o Corrected serum calcium ≤ 12.5 mg/dL (≤ 3.1 mmol/L) or free ionized calcium ≤ 6.5 mg/dl (≤ 1.6 mmol/L). 11. Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening and prior to the first dose of cyclophosphamide and fludarabine using a highly sensitive serum pregnancy test (β human chorionic gonadotropin [β-hCG]). 12. WOCBP are required to meet the following criteria:
• Must agree to practice a highly effective method of contraception (failure rate of < 1% per year when used consistently and correctly) and agree to remain on a highly effective method of contraception from the time of signing the informed consent form (ICF) until 1 year after receiving CB-011 infusion. Examples of highly effective contraceptives include:
o User-independent methods: 1) implantable progestogen-only hormone contraception associated with inhibition of ovulation; 2) intrauterine device; intrauterine hormone-releasing system; 3) vasectomized partner; and
o User-dependent methods: 1) combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral or intravaginal or transdermal; 2) progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable). Note: Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method. 13. Men who are sexually active: − With a WOCBP must agree to use a highly effective barrier method of contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) from the time of signing the ICF until 1 year after receiving a CB-011 infusion. − With a pregnant woman must use a condom. 14. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 1 year after the last dose of study treatment. 15. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Exclusion Criteria
Prior treatment with CAR-T cell therapy directed at any target.
Diagnosed or treated for invasive malignancy other than multiple myeloma, except:
• Malignancy treated with curative intent and with no known active disease present for > 2 years before enrollment
• Adequately treated non-melanoma skin cancer without evidence of active disease. 3. Prior antitumor therapy as follows, prior to lymphodepleting chemotherapy:
• Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less
• Monoclonal antibody treatment for multiple myeloma within 21 days
• Anti-BCMA bispecific T-cell engager (BiTE) or antibody drug conjugate (ADC) within 90 days
• Cytotoxic therapy within 14 days
• PI therapy within 14 days
• IMiD therapy within 7 days
• Radiotherapy within 14 days; however, if the radiation portal covered < 5% of the bone marrow reserve, the patient is eligible irrespective of the end date of radiotherapy. 4. Toxicity from previous anticancer therapy must resolve to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy. 5. The following cardiac conditions: • New York Heart Association (NYHA) stage III or IV congestive heart failure • Myocardial infarction or coronary artery bypass graft (CABG) < 6 months prior to enrollment • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration • History of severe non-ischemic cardiomyopathy • Impaired cardiac function (LVEF < 45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan. 6. Received a cumulative dose of corticosteroids equivalent to ≥ 70 mg of prednisone within the 7 days prior to lymphodepletion. 7. Received either of the following:
• An allogeneic stem cell transplant within 6 months before lymphodepletion. Patients who received an allogeneic transplant > 6 months prior, have discontinued immunosuppressive medications for 6 weeks without signs of GvHD
• An autologous stem cell transplant < 12 weeks before lymphodepletion. 8. Known active or prior history of CNS involvement or exhibits clinical signs of meningeal involvement of MM (extradural mass emanating from skull or spine causing extrinsic mass effect are not excluded). 9. Stroke or seizure within 6 months of signing ICF. 10. Active plasma cell leukemia at Screening (≥ 5% plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis. 11. Seropositive for or history of human immunodeficiency virus (HIV). 12. Vaccinated with live, attenuated vaccine within 4 weeks prior to lymphodepletion. 13. Hepatitis B infection (see Appendix 8). 14. Hepatitis C infection (defined as anti-hepatitis C virus [HCV] antibody-positive or HCV-RNA positive) or known to have a history of hepatitis C. For patients with known history of HCV infection, confirmation of sustained virologic response is required for study eligibility, defined as ≥ 24 weeks after completion of antiviral therapy. 15. Supplemental oxygen use to maintain adequate oxygenation.
• Adequate oxygenation defined as oxygen saturation > 92% on room air with ≤ Grade 1 dyspnea 16. Known life-threatening allergies, hypersensitivity, or intolerance to CB-011 or its excipients. 17. Serious underlying medical condition, such as:
• Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection;
• Active autoimmune disease or a history of autoimmune disease within 3 years; or
• Overt clinical evidence of dementia or altered mental status. 18. Any issue that would impair the ability of the patient to receive or tolerate the planned treatment at the investigational site, to understand informed consent, or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being of) or that could prevent, limit, or confound the protocol-specified assessments. 19. Pregnant, breast feeding, or planning to become pregnant while enrolled in this study or within 1 year after receiving study treatment. 20. Plans to father a child while enrolled in this study or within 1 year after receiving study treatment. 21. Major surgery within 2 weeks prior to lymphodepletion or has surgery planned during the study or within 2 weeks after study treatment administration (unless conducted under local anesthesia).
