Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma

NCT03201250 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 0434-17-FB
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief Summary

In the currently proposed phase I/II study, the investigators aim to treat patients with relapsed and/or relapsed refractory Multiple Myeloma who have progressed on carfilzomib-based therapy with an FDA approved c-MET inhibitor, cabozantinib.

Conditions

Multiple Myeloma; Refractory Multiple Myeloma; Relapsed/Refractory Multiple Myeloma

Keywords

carfilzomib; cabozantinib; proteasome inhibitor; resistance

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of Daily Cabozantinib Given

  The investigators will study three dose levels using the 3+3 algorithm. MTD will be assess with dose limiting toxicities (DLTs) based solely on adverse events that occur during cycle 1.

  1 cycle (approximately 28 days)

• Overall Response Rate (ORR)

  Per International Myeloma Working Group (IMWG) Uniform Response Criteria guidelines as assessed by laboratory blood tests: Complete Response (CR), negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, \<5% plasma cells in bone marrow; Stringent Complete Response (sCR), same as CR plus normal serum free light chain (FLC) ratio and absence of clonal plasma cells; Very Good Partial Response (VGPR), serum and urine M-component still detectable by immunofixation or \>/= 90% reduction in serum M-component plus a urine M component of, 100mg per 24hrs; Partial Response (PR) ≥ 50% reduction of the serum M-protein and 24 hour urinary M-protein by ≥ 90%, or to \< 200 mg per 24 hours. If serum and urine M-protein are not measurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required OR If FLC is also not informative, ≥ 50% reduction in bone marrow plasma. ORR includes following only: CR+sCR+VGPR+PR

  2 cycles (approximately 56 days)

Secondary Outcomes (1)

• Response Durability Assessed by Progression Free Survival (PFS)

  variable, defined by individual response durability in individual patients who would stay on therapy until disease progression

Study Arms (1)

Treatment

EXPERIMENTAL

Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23)

Drug: Cabozantinib

Interventions

Cabozantinib DRUG

Cabozantinib: Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 Phase II: One of phase I dosing levels identified as MTD, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)

Also known as: carfilzomib, dexamethasone

Treatment

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Previously diagnosed symptomatic multiple myeloma (MM), with all 3 of the following IMWG criteria, except as noted:
• Clonal bone marrow plasma cells ≥ 10%
• A monoclonal protein in either serum or urine
• Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (to include one of the following)
• Hypercalcemia (corrected calcium \> 2.75 mmol/L or 11.5 mg/dL); OR
• Renal insufficiency attributable to myeloma (serum creatinine \>1.9 mg/dL); OR
• Anemia; normochromic, normocytic with a hemoglobin value ≥2 g/dL below the lower limit of normal, or a hemoglobin or \<10 g/dL; OR
• Bone lytic lesions, severe osteopenia or pathologic fractures.
• Patients with a biopsy-proven plasmacytoma and either a serum or urine monoclonal protein will also be considered to have met the diagnostic criteria for multiple myeloma in the absence of clonal marrow plasmacytosis of ≥ 10%.
• Patient with bone marrow plasma cells of ≥ 60% or serum free light chain ratio of ≥ 100 will also be considered to have met the diagnostic criteria for multiple myeloma.
• Patients must have measurable disease, with at least one of the following:
• Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease
• M-protein or total serum IgD ≥0.5 g/dL for IgD disease
• Urinary M-protein excretion of ≥200 mg over a 24-hour period
• Involved free light chain level ≥10 mg/dL, with an abnormal free light chain ratio

You may not qualify if:

• Patients who are receiving any concurrent investigational agent with known or suspected activity against MM, or those whose adverse events due to agents administered more than 4 weeks earlier have not recovered to grade 0 or 1.
• Patients who have known CNS involvement with MM
• Patients who have previously been treated with another agent targeting the MUC20/c-Met axis, including either monoclonal antibodies to MUC20 or c-Met, or small molecule inhibitors of c-Met.
• Patients with a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib.
• Chronic concomitant treatment with strong CYP3A4 inhibitors (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) should be avoided because it may significantly decrease cabozantinib concentrations. If patients are taking any strong CYP3A4 inhibitors, alternate medications with no or minimal CYP3A4 inhibitors should be sought prior to trial enrollment.
• Uncontrolled or ongoing/active infection, or patients with the following history: recent history of hemorrhage or hemoptysis; dehiscence or wound healing complications requiring medical intervention; severe hypertension that cannot be controlled (blood pressure of \> 150 systolic or \> 100 diastolic mm) with anti-hypertensive therapy within 7 days of first dose of therapy.
• Pregnant or lactating women
• Patients with non-secretory MM, active plasma cell leukemia, defined as either having 20% of peripheral WBC comprised of CD138+ plasma cells, or an absolute plasma cell count of 2 x 109/L, known amyloidosis, or known POEMS syndrome
• Patients who have required plasmapheresis and exchange less than 2 weeks prior to initiation of therapy with cabozantinib
• Patients with known moderate or severe hepatic impairment, active hepatitis A, B, and/or C infection
• Patients with a "currently active" second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for \>5 years, and are considered by their physician to be at less than 30% risk of relapse. Also, patients with basal cell carcinoma of the skin, superficial carcinoma of the bladder, carcinoma of the prostate with a current PSA value of \<0.5 ng/mL, or cervical intraepithelial neoplasia are eligible. Patients who are on hormonal therapy for a history of either prostate or breast cancer may enroll, if there has been no evidence of disease progression during the previous 3 years.
• Allergy to carfilzomib or cabozantinib or any excipients
• Uncontrolled intercurrent illness including medical, psychiatric, cognitive or other conditions, psychiatric illness/social situations that would compromise the patient's ability to understand the patient information, to give informed consent, to comply with the study protocol or to complete the study or, in the judgment of the Principal Investigator, would make the patient inappropriate for study participation.
• The subject has experienced any of the following:
• clinically-significant GI bleeding within 6 months before the first dose of study treatment;

Sponsors & Collaborators

• University of Nebraska: lead
• M.D. Anderson Cancer Center: collaborator

Study Sites (2)

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

cabozantinib; carfilzomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Muhamed Baljevic, MD
• Organization: Vanderbilt University Medical Center

muhamed.baljevic@vumc.org

615-936-8422

Study Officials

• Muhamed Baljevic, MD

  University of Nebraska

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2017
• First Posted: June 28, 2017
• Study Start: February 21, 2018
• Primary Completion: April 12, 2021
• Study Completion: April 12, 2021
• Last Updated: September 8, 2023
• Results First Posted: December 23, 2022

Record last verified: 2023-08

Locations

US (2)