Ph I Study in Adult Patients With Relapsed or Refractory Multiple Myeloma

This is a Phase I, first-in-human (FIH), open-label, non-randomized, multi-center study to explore the safety, tolerability, pharmacokinetics and preliminary antitumor activity of NMS-03597812 in adult patients with RRMM who have exhausted standard treatment options that are expected to provide meaningful clinical benefit or for whom standard therapy is considered unsuitable.


Eligibility Criteria:
Inclusion Criteria:

1. Patients must have a confirmed diagnosis of relapsed or relapsed and refractory multiple myeloma (as per IMWG criteria)
2. Patients must have exhausted available therapeutic options that are expected to provide meaningful clinical benefit, either through disease relapse, treatment refractory disease, intolerance or refusal of the therapy.
3. Patients must have received at least three prior lines of therapy as defined by IMWG, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.
4. Patients must have progressive/refractory disease to the last line of therapy.
5. Patients must have measurable disease, defined as any of the following:serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis, ≥200 mg of monoclonal protein in urine on 24-h electrophoresis, or serum immunoglobulin free light chain ≥10 mg/dL with abnormal free-light-chain ratio.
6. Adult (age ≥18 years) patients.
7. Karnofsky performance status ≥60%.
8. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTCAE version 5.0 Grade ≤1 or according to inclusion criterion 9.
9. Adequate hematological profile, renal, hepatic and pancreatic functions
10. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within the screening period prior to start of the study drug.
11. Patients must use effective contraception or abstinence. Female patients of childbearing potential must agree to use effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment. Male patients must be surgically sterile or must agree to use effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment.
12. Ability to swallow capsules intact (without chewing, crushing, or opening).
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures.
14. Signed and dated IRB/EC-approved Informed Consent

Exclusion Criteria:

1. Current enrollment in another interventional clinical study.
2. Diagnosis of primary refractory multiple myeloma defined as disease that is non-responsive in patients who have never achieved a minimal response or better with any therapy
3. Diagnosis of plasma cell leukemia, Waldenstrom's macroglobulinemia or amyloidosis.
4. Diagnosis of non-secretory myeloma.
5. Known central nervous system (CNS) involvement by multiple myeloma.
6. Known history of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome.
7. Currently active second malignancy, except for adequately treated basal or squamous cell skin cancer and/or conebiopsied in situ carcinoma of the cervix uteri and/or superficial bladder cancer.
8. Autologous stem cell transplant ≤3 months prior to starting NMS-03597812.
9. Prior allogeneic hematopoietic stem cell transplant (HSCT) with either standard or reduced intensity conditioning ≤6 months prior to starting NMS-03597812.
10. Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment. Patients who experienced GVHD requiring immunosuppressive treatment, must have stopped immunosuppressive treatment \>3 months prior to starting NMS-03597812.
11. Any anticancer agent within 3 weeks (6 weeks for immunotherapy or nitrosoureas).
12. Prior CAR-T cell \<3 months prior to starting NMS-03597812.
13. Concomitant oral prednisone(or equivalent)\>10 mg/day. Doses of corticosteroid must have been stable for at least 7 days before startingNMS-03597812.
14. Major surgery within 4 weeks before treatment start.
15. Radiotherapy within 3 weeks prior to starting NMS-03597812. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy.
16. Patient with evidence of clinically significant mucosal or internal bleeding.
17. Patient platelet transfusion refractory.
18. History of pancreatitis or current alcohol abuse.
19. Uncontrolled diabetes.
20. Patients with QTc interval ≥ 480 milliseconds or with risk factors for torsade de pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of prolonged QTc interval or family history of long QT syndrome). For patients receiving treatment with concomitant medications known to prolong the QTc interval, replacement with another treatment should be considered. If replacement or discontinuation is not clinically feasible, a careful risk/benefit evaluation should be performed prior to enrollment.
21. Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.
22. Known hypersensitivity to any of the components of the NMS-03597812 drug product.
23. Known hypersensitivity to steroids or any of the components of the dexamethasone drug product (applies only to the expansion cohort testing NMS-03597812 in combination with dexamethasone).
24. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
25. Uncontrolled bacterial, viral, or fungal infections including: known infection with HIV, HBV and/or HCV; patients who are seropositive following HBV vaccine are eligible.
26. Known active gastrointestinal disease (e.g., documented gastrointestinal ulcer, Crohn's disease, ulcerative colitis or short gut syndrome) or other malabsorption syndromes that would impact drug absorption or represent a contra-indication for the treatment with dexamethasone (NMS-03597812 and dexamethasone expansion cohort).
27. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
28. Patient who are receiving concomitant medications that are strong inducers or inhibitors of CYP34A and CYP2C9 that cannot be replaced with alternative therapy.
29. Patients who are receiving concomitant medications that are sensitive substrates of CYP3A4 and CYP2D6 with narrow therapeutic window that cannot be replaced with alternative therapy.