Tasquinimod Alone and in Combination with Standard Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma
This phase I trial is to find out the best dose, possible benefits and/or side effects of tasquinimod alone and in combination with standard therapy in treating multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Tasquinimod may work by blocking the action of S100A9, a protein produced by other cells in the bone marrow when they are stimulated by myeloma cells. S100A9 may allow myeloma cells to survive and grow. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as lenalidomide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tasquinimod alone or in combination with standard therapy may be effective in treating patients with multiple myeloma.
Inclusion Criteria
- Signed informed consent obtained prior to undertaking any study-related procedures
- 18 years of age or older
- Multiple myeloma (MM) diagnosed according to International Myeloma Working Group (IMWG) criteria
- Subjects must have measurable disease. In Arms A2 and B2 (expansion cohorts), measurable disease is defined by at least 1 of the following 3 measurements: serum M-protein >= 1 g/dL (>= 10 g/L), urine M-protein >= 200 mg/24 hours, involved free light chain level >= 10 mg/dL (>= 100 mg/L), provided that the serum free light chain ratio is abnormal
- In Arms A1 and B1 (dose escalation cohorts), measurable disease is defined as above OR at least one of the following: bone marrow plasma cells comprising >= 30% of bone marrow cellularity or at least one extramedullary plasmacytoma on clinical exam or cross sectional imaging with a single diameter of >= 2 cm. Multiple myeloma relapsed or refractory after at least one prior line of anti-multiple myeloma therapy. Refractory is defined as disease progression on therapy, or progression within 60 days of last therapy
- In arms A1, A2, and B1 (single agent tasquinimod and dose escalation of IRd+ tasquinimod [T] combination): refractory disease to, intolerant of, or have a contraindication to therapy with lenalidomide, pomalidomide, bortezomib, carfilzomib, and an anti-CD38 monoclonal antibody (e.g. daratumumab)
- In arm B2 (expansion cohort of IRd+T combination): refractory disease to the most recent combination of an Imid and proteasome inhibitor. Refractory is defined as disease progression on therapy, progression within 60 days of last therapy, or failure to achieve at least a minimal (25%) response after at least 2 full cycles of therapy
- Hemoglobin >= 8 g/dL (no transfusions allowed within 72 hours of qualifying laboratory value) (within 7 days of the start of study treatment)
- Absolute neutrophil count (ANC) >= 1,000/mm^3 (no granulocyte colony stimulating factors [G-CSF or granulocyte-macrophage colony stimulating factor (GM-CSF)] allowed within 1 week and no pegylated G-CSFs allowed within 3 weeks of measurement of ANC) (within 7 days of the start of study treatment)
- Platelet count >= 75,000/mm^3 without growth factor support (no transfusions allowed within 72 hours of qualifying laboratory value); platelet count >= 50,000/mm^3 in subjects with plasma cells comprising > 50% of bone marrow cellularity (within 7 days of the start of study treatment)
- Total bilirubin =< 1.5 times the upper limit of the normal range (ULN), unless elevated bilirubin is due to unconjugated hyperbilirubinemia from Gilbert’s syndrome (within 7 days of the start of study treatment)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 times ULN (within 7 days of the start of study treatment)
- Calculated creatinine clearance >= 30 mL/min, OR serum creatinine < 2.0 mg/dL (within 7 days of the start of study treatment)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Life expectancy of at least 3 months
- For women of childbearing potential, a negative serum or urine pregnancy test must be documented prior to first administration of study treatment
- For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use two methods of contraception one of which must be highly effective (hormonal implant, combined oral contraceptives, intrauterine device, vasectomized partner, bilateral tubal occlusion or complete avoidance of heterosexual intercourse), for 1 month before start of study treatment, during the treatment period and for 4 months after the last dose of study treatment
- For men: agreement to use a barrier method of contraception for 1 month before start of study treatment, during the treatment period and for 6 months after the last dose of study treatment
Exclusion Criteria
- Failure to have fully recovered (i.e. to grade 1 or previous baseline) from clinically significant adverse effects of prior chemotherapy (examples of adverse effects that are not clinically significant include alopecia and lymphopenia)
- Active graft versus host disease
- Treatment with any of the following: * Cytotoxic chemotherapy within 3 weeks prior to the initiation of study treatment * Proteasome inhibitors, Imids, or monoclonal antibodies within 2 weeks prior to the initiation of study treatment * Experimental therapy within 4 weeks or 5 half-lives, whichever is shorter * Systemic corticosteroids >= 10 mg prednisone or equivalent within 7 days prior to the initiation of study treatment * Radiotherapy within 7 days prior to initiating study treatment * Plasmapheresis within 4 weeks prior to the initiation of study treatment * Tasquinimod at any time
- Known central nervous system involvement by myeloma
- Diagnosis of SMM (smoldering multiple myeloma)
- Diagnosis of POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome
- Active plasma cell leukemia (defined as either >= 20% of peripheral white blood cells comprised of plasma/CD138+ cells or an absolute count of >= 2 x 10^9)
- Symptomatic primary (AL) amyloidosis
- Diagnosis of myelodysplastic syndrome or myeloproliferative syndrome
- Active other malignancy, defined as the presence of another malignancy that is not currently in remission and either (1) is causing symptoms or (2) requires ongoing therapy
- Major surgery within 4 weeks prior to initiating study treatment
- Evidence of severe or currently uncontrolled cardiovascular condition (e.g. cardiac amyloidosis, angina, hypertension, peripheral vascular disease, congestive heart failure class III or IV of the New York Heart Association [NYHA] classification, cardiac arrhythmia, acute coronary syndrome, myocardial infarction, cerebrovascular accident, transient ischemic attack, or limb claudication) within 6 months prior to initiating study treatment
- Ongoing or active systemic infection that requires systemic antibiotic or parenteral anti-infective therapy
- Active tuberculosis, active hepatitis A, B or C virus infection, or known human immunodeficiency virus (HIV) positive
- History of pancreatitis
- History of malabsorption or other condition that would interfere with absorption of study drugs
- Systemic treatment within 14 days prior to the initiation of study treatment with any of the following moderate or strong inhibitor or moderate or strong inducer of cytochrome P-3A4 (CYP3A4): imidazoles (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), macrolides (e.g., erythromycin), rifampicin, rifabutin, phenytoin, carbamazepine, St. John's wort
- Need for ongoing therapy with any of the following drug substances of narrow therapeutic range that are metabolized mainly by CYP3A4: alfentanil, fentanyl, quinidine, astemizole, terfenadine, sirolimus, tacrolimus, cyclosporine, cisapride and ergotamine
- Need for ongoing therapy with any of the following drug substances of narrow therapeutic range metabolized mainly by CYP1A2: duloxetine, alosetron, theophylline, tizanidine and ondansetron
- Ongoing treatment with warfarin, unless the international normalized ratio (INR) is =< 3.0
- For subjects enrolled on the IRd combination arms, prior dose-limiting toxicity with lenalidomide or ixazomib or absolute contraindication to concomitant thrombosis prophylaxis
- Peripheral neuropathy grade >= 2 (National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE])
- Known hypersensitivity to tasquinimod or any excipients in the study treatments
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (˃ 5 mIU/mL)
- Any other condition that would, in the investigator’s judgment, contraindicate subject’s participation in the clinical study due to safety concerns or compliance with clinical study procedures e.g. any uncontrolled disease such as pulmonary disease, infection or seizure disorder; intestinal obstruction, inability to swallow medication, any altered mental status or psychiatric condition that would interfere with the understanding of the informed consent
- Prior inclusion in this study
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04405167.
PRIMARY OBJECTIVE:
I. To determine the optimal dose and schedule of tasquinimod as a single agent and in combination with ixazomib, lenalidomide, and dexamethasone in subjects with relapsed/refractory multiple myeloma.
SECONDARY OBJECTIVES:
I. To obtain a preliminary assessment of the toxicity profile of tasquinimod as a single agent and in combination with ixazomib, lenalidomide, and dexamethasone in subjects with relapsed/refractory multiple myeloma (RRMM).
II. To evaluate preliminary efficacy of tasquinimod as a single agent in subjects with RRMM.
III. To evaluate preliminary efficacy of tasquinimod when administered in combination with ixazomib, lenalidomide, and dexamethasone in subjects with RRMM that is refractory to the most recent proteasome inhibitor (PI)/immunomodulatory drug (Imid) combination.
IV. To determine whether the exposure of tasquinimod, when administered alone or in combination with ixazomib, lenalidomide, and dexamethasone, in subjects with RRMM, is similar to previously tested groups of patients.
V. To evaluate changes in the bone marrow microenvironment during tasquinimod therapy (as a single agent or in combination with ixazomib, lenalidomide [Revlimid], and dexamethasone [IRd]) as a biomarker of tasquinimod response.
OUTLINE: This is a dose-escalation study of tasquinimod followed by a dose-expansion study. Patients are assigned to 1 of 4 arms.
ARM A1 (DOSE-ESCALATION): Patients receive tasquinimod orally (PO) once daily (QD) at 1 of 5 dose levels on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM A2: (DOSE-EXPANSION): Patients receive tasquinimod PO QD at the best dose found in Arm A1 on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM B1 (DOSE-ESCALATION): Patients receive tasquinimod PO QD at 1 of 5 dose levels on days 1-28. Patients also receive ixazomib PO QD on days 1, 8, and 15, lenalidomide PO QD on days 1-21, and dexamethasone PD QD on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM B2 (DOSE-EXPANSION): Patients receive tasquinimod PO QD at the best dose found in Arm B1 on days 1-28. Patients also receive ixazomib, lenalidomide, and dexamethasone as in Arm B1.
After completion of study treatment, patients are followed up for 30 days.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of Pennsylvania/Abramson Cancer Center
Principal InvestigatorDan T Vogl
- Primary IDUPCC 45419
- Secondary IDsNCI-2020-13311
- ClinicalTrials.gov IDNCT04405167