IRB Study Number 26-150
Status Recruiting
Phase Phase 2
Locations Fairview Hospital, Hillcrest Hospital, Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
This is a Phase II, open-label, multicenter study to evaluate the efficacy and safety of inobrodib in combination with pomalidomide and dexamethasone (InoPd) in patients with relapsed and refractory multiple myeloma (RRMM).
Patients must be 18 years or older and be refractory to least one proteosome inhibitor (PI), one anti-CD38 monoclonal antibody (mAb) and pomalidomide. Patients must also be previously treated with an approved bispecific T-cell engager [TCE].
Approximately 100 patients will be treated with 20 mg of inobrodib administered orally twice daily (b.i.d.) 4 days on / 3 days off for each 28-day cycle. Pomalidomide and dexamethasone will be administered as per standard of care (SoC), i.e., with a starting dose of 4 mg orally once daily on Day 1 to 21 of each 28-day cycle for pomalidomide, and 40 mg orally once daily on Days 1, 8, 15 and 22 for each 28-day cycle for dexamethasone. Study treatment should be continued until disease progression, initiation of new anticancer therapy, unacceptable toxic
Inclusion Criteria
Patients must meet all the following criteria to be eligible for the study.
General eligibility criteria:
- Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses
- Willing and able to participate in all required evaluations/procedures and adhere to prohibitions/restrictions specified in this study protocol
- Male or female ≥18 years of age
- Eastern Co-operative Oncology Group (ECOG) performance status of 0 to 2
- Viral status (Hepatitis B, C and human immunodeficiency virus [HIV]) established at baseline Diagnosis and disease characteristics:
- Prior diagnosis of MM as defined according to IMWG criteria and relapsed or refractory to the last line of therapy Note: Refractory is defined as follows: disease progression while on therapy OR within 60 days of the last dose in any line of therapy, independent of response OR failure to achieve at least a minimal response after at least two complete cycles of therapy.
- Measurable disease based on IMWG criteria, defined as the presence of at least ONE of the following:
a. Serum M-protein >0.5 g/dL by serum protein electrophoresis (SPEP), or
b. Urinary M-protein excretion >200 mg/24 hours by urine protein electrophoresis (UPEP), or
c. Serum immunoglobulin free light chain (FLC) ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65) - Refractory to pomalidomide
- Refractory or intolerant to at least one PI (e.g., bortezomib, carfilzomib, ixazomib)
- Refractory to at least one anti-CD38 mAb (e.g., daratumumab, isatuximab).
- Previously treated with an approved bispecific TCE (e.g., teclistamab, elranatamab, linvoseltamab, talquetamab)
- Documented disease progression following the most recent anti-myeloma therapy, or failure to achieve at least a minimal response after 2 full cycles of therapy (or by 3 months after CAR T cells or autologous stem cell transplant)
Organ system function: - Adequate hematological function:
a. Hemoglobin level ≥8.0 g/dL (screening result must be independent of red blood cell transfusion for at least 7 days; recombinant human erythropoietin use is permitted)
b. Platelet count ≥75 × 109/L (75,000 cells/mm3) in patients in whom <50% of bone marrow nucleated cells are plasma cells, and platelet count ≥50 × 109/L (50,000 cells/mm3) in patients in whom ≥50% of bone marrow nucleated cells are plasma cells; screening result must be independent of platelet transfusion for at least 7 days
c. Absolute neutrophil count ≥1.0 × 109/L (≥1000 cells/mm3; growth factor support is permitted but screening result must be without support for at least 7 days), OR ≥750 cells/mm3 in patients with Duffy null phenotype (confirmed at screening e.g., genetic test to detect the normal variation in the ACKR1 gene, and adequately documented by the Investigator) if this is considered their normal baseline - Adequate hepatic function:
a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN)
b. Total bilirubin ≤1.5 × ULN (except in patients with congenital bilirubinemia, such as Gilbert’s syndrome in which case total bilirubin ≤3 × ULN is required) - Adequate renal function:
a. Creatinine clearance ≥30 mL/min as measured or calculated by Cockcroft-Gault equation
b. Normal sodium levels OR no worse than Grade 1 hyponatremia (≥130 mmol/L)
Contraception: - For the duration of the study and for 4 weeks after the last study medication administration, male patients (including those who have had a vasectomy) must be willing to use barrier contraception i.e., latex or synthetic condoms (with spermicide, if locally approved for use) with all sexual partners. Where the sexual partner is a WOCBP who is not using effective contraception, who is pregnant, or who is breastfeeding, men must use barrier contraception (with spermicide, if locally approved for use) and another form of contraception during the study and for 6 months after the last dose of study medication (see Appendix C).
- WOCBP must agree to use two measures of contraception, one of which must be highly effective (if sexually active) during the study and for 6 months after the last dose of study medication. In addition, she must not be breast feeding and must have two negative serum pregnancy tests prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential (see Appendix C).
Exclusion Criteria
Patients who meet any of the following criteria are not eligible for the study.
Prior or concomitant treatments
- Use of any investigational agent, chemotherapy, immunotherapy or anticancer agent from a previous clinical study within 14 days or 5 half-lives of first dose of study treatment, whichever is shortest; any antibody based therapy within 30 days
- Prior treatment with p300/CBP bromodomain inhibitors
- History of severe allergic or anaphylactic reactions or any known severe allergies to any active or inactive ingredients in the study medications (inobrodib, pomalidomide, dexamethasone) or any prior immunomodulatory drug (lenalidomide, thalidomide)
- Treatment with any of the following:
a. Strong inducers of CYP3A4 taken within 2 weeks or 5 half-lives, whichever is longer, of the first dose of study treatment or whilst on study treatment
b. Strong inhibitors of CYP3A4 and/or P-gp taken within 7 days or 5 half-lives, whichever is longer, of the first dose of study treatment or while on study treatment, including the consumption of grapefruit or grapefruit juice
c. CYP3A4 and/or CYP2B6 and/or P-gp and/or organic anion transporter polypeptide (OATP)1B1 sensitive substrates and substrates with narrow therapeutic index taken within 2 weeks of the first dose of study treatment and during Cycle 1
Note: Patients may receive pravastatin or fluvastatin (with monitoring for potential toxicities), or atorvastatin or simvastatin at 10 mg daily dose only.
d. CYP2C8 sensitive and moderately sensitive substrates taken within 2 weeks of the first dose of study treatment and during Cycle 1
e. Strong CYP1A2 inhibitors should be avoided at initiation and during first cycle. If required, concomitant use is possible with at least 50% reduction of pomalidomide dose
f. Herbal medications taken within 7 days of the first dose of study treatment (4 weeks for St John’s wort) or while on study treatment
g. Steroid use not exceeding 20 mg weekly dexamethasone dose or approximate equivalent within 2 weeks of the first dose of study treatment. Replacement therapy steroids (even exceeding the above daily dose), given in the context of a transfusion, and inhaled, nasal, topical and ophthalmic steroids are allowed
h. Medications with known risk of QT/QTc interval prolongation should be avoided concomitantly with inobrodib unless essential in clinical management of the patient. If unavoidable, additional monitoring of potential QT/QTc interval prolongation is warranted.
i. Major surgery within 4 weeks of the first dose of study treatment
j. Live vaccine within 4 weeks of study treatment and thereafter until B-cell recovery
Prior or concomitant conditions - Plasma cell leukemia, Waldenström’s macroglobulinemia, amyloidosis, polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome
- Stem cell transplant within 12 weeks or active graft versus host disease (GvHD)
- With the exception of alopecia, and Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 neuropathy, any unresolved clinically significant toxicities from prior therapy >Grade 1 at the time of starting study treatment.
- Active or unresolved spinal cord compression or central nervous system infiltration
- Active malignancies (progressing or requiring change in treatment) in the last 24 months other than multiple myeloma, except for the following exceptions.
Adequate treatment must have been applied and condition considered completely cured:
a. Carcinoma in situ or skin cancer (melanomatous or otherwise)
b. Non-invasive cervical cancer
c. Non-muscle invasive bladder cancer
d. Breast cancer – ductal or lobular carcinoma in situ; localized breast cancer and receiving hormonal agents and considered very low risk
e. Localized prostate cancer (N0M0) deemed to have a very low risk of recurrence, e.g., Gleason score of 6 or 3+4, or receiving androgen deprivation therapy and considered very low risk
f. Malignancy that is considered cured with minimal risk of recurrence or in remission for 2 years - Active infection requiring treatment within the last 14 days. Any active infections must be resolved at least 14 days prior to enrolment
- Any evidence of severe or uncontrolled systemic disease, e.g.,:
a. Current unstable or uncompensated respiratory or cardiac conditions;
b. Recent history of significant cardiac incidents, e.g., significant cardiac dysfunction (congestive heart failure [NY Heart Association Class III or IV]; myocardial infarction within 12 months of starting study; unstable or poorly controlled angina pectoris); history of risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or clinically significant arrhythmia;
c. Uncontrolled diabetes;
d. History of, or active, bleeding diatheses;
e. Uncontrolled active systemic infection, including hepatitis B, hepatitis C and HIV, or active SARS-CoV2
f. Cirrhosis or current unstable liver or biliary disease
g. Other surgical, medical or psychiatric conditions or laboratory abnormality that may increase the risk of study participation or, in the Investigator’s judgment, make the patient inappropriate for the study. - Repeatable QT interval corrected using Fridericia’s formula (QTcF) prolongation (>470 msec)
Other exclusions - Female patients who are pregnant or breast-feeding at any time during the study
- Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
