Cabozantinib in Treating Patients with Refractory Multiple Myeloma Resistant to Carfilzomib

Status: Active

Description

This phase I / II trial studies the best dose cabozantinib and how well it works when given together with carfilzomib and dexamethasone in treating patients with multiple myeloma that does not respond treatment and is resistant to carfilzomib. Cabozantinib and carfilzomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib together with carfilzomib and dexamethasone may reverse the resistance to carfilzomib.

Eligibility Criteria

Inclusion Criteria

  • Patients must have been previously diagnosed with histologically or cytologically confirmed symptomatic multiple myeloma, which require the presence of all three of the following International Myeloma Working Group 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 (magnetic resonance imaging [MRI], computed tomography [CT] or positron emission tomography [PET]/CT with > 1 focal lesions >= 5 mm in size), 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, as defined by at least one of the following: * Serum monoclonal protein level >= 0.5 g/dL for IgG, IgA, or IgM disease * Monoclonal 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, along with an abnormal free light chain ratio
  • Patients must have had at least two, but not more than four prior lines of therapy for their disease, with lines of therapy being separated by the presence of documented disease progression; using this definition, treatment with induction therapy, followed by high dose chemotherapy and autologous stem cell transplantation, and finally by maintenance therapy, would constitute one line, provided that multiple myeloma did not meet criteria for progression at any time during this period
  • Patients eligible for this trial will be those who have failed carfilzomib either as a single agent as the last form of therapy, or carfilzomib in combination with dexamethasone, or carfilzomib in combination with revlimid and dexamethasone; given the potential for compounding/worsening toxicities with the addition of cabozantinib to carfilzomib, patients eligible for the trial will have to have had very good tolerance to carfilzomib in the context of described regimens, with resolved prior toxicity to grade 1 or better, and no toxicities due to carfilzomib that required dose reductions to less than 27 mg/m^2
  • Patients must have disease that has relapsed after carfilzomib therapy, with progressive disease (PD) being defined as an increase of 25% from the lowest response value in any one or more of the following: * Serum M-component (the absolute increase must be >= 0.5 g/dL) and/or * Urine M-component (the absolute increase must be >= 200 mg/24 hours) and/or * Only in patients without a measurable serum and urine M protein level: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase) must be > 10 mg/dL * Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder Patients with relapsed disease will be considered to be those who have had progression, as defined above, off of any therapy, and who completed their therapy more than 60 days prior to the finding of progression; patients with relapsed and refractory disease will be considered to be those who have had progression, as defined above, while still on their last line of therapy, or who progressed within 60 days of finishing their most recent therapy
  • Patients must have completed their most recent drug therapy directed at multiple myeloma in the following timeframes: * Chemotherapy, biological therapy, immunotherapy, or an investigational therapy at least 3 weeks prior to starting cabozantinib * Corticosteroids at least 3 weeks prior to starting cabozantinib, except for a dose equivalent to dexamethasone of =< 4 mg/day * Nitrosoureas, nitrogen mustards, mitomycin C, or monoclonal antibodies at least 6 weeks prior to starting cabozantinib * Autologous stem cell transplantation at least 12 weeks prior to starting cabozantinib * Allogeneic stem cell transplantation at least 24 weeks prior to starting cabozantinib, and these patients must also not have moderate to severe active acute or chronic graft versus host disease
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Karnofsky >= 60%)
  • Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without growth factors within 1 week of the initiation of treatment
  • Total white blood cell count (WBC) >= 2,000 cells/mm^3 without growth factors within 1 week of the initiation of treatment
  • Hemoglobin >= 8 g/dL without red blood cell transfusions within 2 weeks of the initiation of treatment
  • Platelet counts of >= 100,000 cells/mm^3 for patients who have bone marrow plasmacytosis of < 50%, or platelets >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%
  • Total bilirubin =< 1.5 times the upper limit of the institutional normal values
  • Total aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times the upper limit of the institutional normal values
  • Serum creatinine within the institutional normal limits, OR if the creatinine is elevated
  • Creatinine clearance (CrCl) >= 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula
  • Worsening urinary paraproteinemia will be considered in the context of International Myeloma Working Group (IMWG) disease response criteria on a monthly basis; any patient with urinary protein (otherwise unrelated to urinary myeloma associated monoclonal [M]-protein) with excretion > 3.5 g/day will be considered to have developed nephrotic-range proteinuria, and will be taken off study
  • Absence of New York Heart Association (NYHA) class II, III, or IV congestive heart failure
  • Absence of uncontrolled angina or hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
  • Absence of the following in the previous 6 months: * Myocardial infarction; * Unstable angina pectoris; * Clinically-significant cardiac arrhythmias; * Stroke (including transient ischemic attack [TIA], or other ischemic event); * Thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter [eg, vena cava filter] are not eligible for this study)
  • Absence of clinically significant bradycardia, or other uncontrolled cardiac arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI) Common Terminology
  • Absence of history of congenital long QT syndrome
  • Patients who have received radiation therapy must have completed this at least 4 weeks prior to starting therapy with cabozantinib, with the following exceptions: * Local radiation therapy to enhance bone healing of a pathologic fracture may have been performed, as long as it was completed at least 2 weeks prior to starting cabozantinib * Local radiation therapy to treat post-fracture pain that is refractory to analgesics may have been performed, as long as it was completed at least 2 weeks prior to starting cabozantinib
  • Patients who have undergone any recent major surgery must have done so at least 4 weeks prior to starting therapy with cabozantinib, with the following exceptions: * Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week prior to starting cabozantinib * Planned elective surgery unrelated to the patient’s diagnosis of multiple myeloma, such as hernia repair, may be allowed, at the discretion of the principle investigator, as long as it was performed at least 2 weeks prior to starting cabozantinib, and patients have recovered fully from this procedure
  • Human immunodeficiency virus (HIV) seropositive patients with acceptable organ function who meet the patient selection criteria, and who are not on combination antiretroviral therapy, and whose absolute CD4+ count is >= 400 cells per cubic millimeter of blood, will be eligible; however, HIV positive patients on combination antiretroviral therapy will be ineligible, because of the potential for pharmacokinetic interactions with cabozantinib
  • Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s); male subjects must agree to not donate sperm for at least 90 days after the last dose of carfilzomib
  • Female subjects of childbearing potential must not be pregnant at screening; female patients must be either postmenopausal, free from menses for >= 2 years, surgically sterilized, or willing to use two adequate barrier methods of contraception to prevent pregnancy, or must agree to abstain from heterosexual activity throughout the study; female patients of childbearing potential must have a negative serum (beta human chorionic gonadotropin [βHCG]) or urine pregnancy test before receiving the first dose of cabozantinib or carfilzomib; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; women of reproductive potential will be counseled to use effective contraceptive measures to prevent pregnancy during treatment with either cabozantinib or carfilzomib; patients shall be advised not to take cabozantinib or carfilzomib treatment while pregnant or breastfeeding; if a patient wishes to restart breastfeeding after treatment, she will be advised to discuss the appropriate timing with her physician
  • Understand and able to willingly provide voluntary written informed consent, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care

Exclusion Criteria

  • Patients who are receiving any concurrent investigational agent with known or suspected activity against multiple myeloma, or those whose adverse events due to agents administered more than 4 weeks earlier have not recovered to a severity of grade 0 or grade 1
  • Patients who have known central nervous system involvement with multiple myeloma will be excluded from this clinical trial
  • 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
  • Cabozantinib is metabolized by CYP3A4; the metabolism and consequently overall pharmacokinetics of cabozantinib could be altered by inhibitors and/or inducers or other substrates of CYP3A4; it is recommended that chronic concomitant treatment with strong CYP3A4 inhibitors (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s wort) or inducers should be avoided; if patients are taking any strong CYP3A4 inhibitors, alternate medications with no or minimal CYP3A4 inhibitors should be sought prior to trial enrolment; while mild inhibitors/inducers of these cytochrome P450 isoenzymes are not specifically excluded, investigators should be aware that cabozantinib exposure may be altered by the concomitant administration of these drugs, and avoidance is also recommended
  • Uncontrolled or ongoing/active infection; patients with the following history will also not be eligible for the trial: patients with a recent history of hemorrhage or hemoptysis; patients with dehiscence or wound healing complications requiring medical intervention; patients with severe hypertension that cannot be controlled (blood pressure of > 150 systolic or > 100 diastolic mmHg) with anti-hypertensive therapy within 7 days of first dose of therapy
  • Pregnant or lactating women are excluded from this study; breastfeeding should be discontinued if the mother is treated with cabozantinib
  • Patients with non-secretory multiple myeloma, active plasma cell leukemia, defined as either having 20% of peripheral white blood cells comprised of CD138+ plasma cells, or an absolute plasma cell count of 2 x 10^9/L, known amyloidosis, or known POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • 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, due to the difficulty that would be faced in assessing the attribution of any events of hepatic toxicity while on cabozantinib therapy
  • Patients with a “currently active” second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled; 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; in addition, 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 will be eligible; finally, patients who are on hormonal therapy for a history of either prostate cancer or breast cancer may enroll, if there has been no evidence of disease progression during the previous three 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; * Gastrointestinal (GI) disorders particularly those associated with a high risk of perforation or fistula formation including: ** Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ** Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization, ** Note: complete healing of an intra-abdominal abscess must be confirmed prior to randomization * Hemoptysis of >= 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment; * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment * Patient who have developed or have had history of pulmonary hemorrhage while on carfilzomib will be excluded (fatal pulmonary hemorrhage has been observed with carfilzomib)
  • The subject has radiographic evidence of cavitating pulmonary lesion(s)
  • The subject has tumor invading or encasing any major blood vessels
  • The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
  • Corrected QT using Fridericia's formula (QTcF) > 500 msec within 1 month before the first dose of study treatment: * Three electrocardiogram (ECG)s must be performed for eligibility determination; if the average of these three consecutive results for QTcF is =< 500 msec, the subject meets eligibility in this regard
  • Inability to swallow intact tablets
  • The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory upper limit of normal (ULN) within 7 days before the first dose of study treatment
  • Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel) * Note: low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted if started > 6 months prior to randomization; LMWH used as therapeutic anticoagulation may increase observed PTT levels in subjects; anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 24 weeks before randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen
  • Subjects who have carfilzomib-related posterior reversible encephalopathy syndrome (PRES) and thrombotic microangiopathy (TMA) should not be challenged with carfilzomib

Locations & Contacts

Nebraska

Omaha
University of Nebraska Medical Center
Status: Active
Contact: Muhamed Baljevic
Phone: 402-559-8562
Email: muhamed.baljevic@unmc.edu

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: Robert Zygmunt Orlowski
Phone: 713-745-8576
Email: rorlowsk@mdanderson.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of daily cabozantinib given on days 1-28 added to a capped dose of carfilzomib of 27 mg/m^2 and capped dose of dexamethasone a 40 mg weekly every 4 weeks for a total of 3 cycles in patients with relapsed and refractory (RR) multiple myeloma (MM) who have lost response to carfilzomib.

II. To estimate the overall response rate (ORR) of patients with RR MM treated with the addition of cabozantinib to carfilzomib.

SECONDARY OBJECTIVES:

I. To identify biological correlates of clinical outcomes and toxicity, including the measurement of MUC20 levels at enrollment and after cycle 2, and activation status of the c-MET/ERK-1/2/ELK1/POMP pathway in primary MM cells at baseline and after each cycles of therapy on protocol, as defined by flow cytometry and gene expression (GEP) data.

II. To estimate progression free survival (PFS), median duration of response (DOR), and median time to next treatment.

TERTIARY OBJECTIVES:

I. To evaluate the symptom burden of RR MM patients undergoing therapy with addition of cabozantinib to carfilzomib in patients who have lost response to proteasome inhibition with carfilzomib, using the M. D. Anderson Symptom Inventory (MDASI) and its multiple myeloma module (MDASI-MM).

II. To evaluate the impact of therapy with cabozantinib in combination with carfilzomib in patients who have lost response to proteasome inhibition with carfilzomib in the RR MM setting on patient reported outcomes using the European Organization for Research on the Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (QLQ-C30; and the myeloma-specific module QLQ-MY20)

III. To evaluate the impact of therapy with cabozantinib for RR MM on the ability to collect stem cells in any patients who go on to undergo subsequent stem cell mobilization.

OUTLINE: This is a dose-escalation study of cabozantinib.

Patients receive cabozantinib orally (PO) on days 1-28, carfilzomib intravenously (IV) over 2-10 minutes on days 1, 2, 8, 9, 15 and 16, and dexamethasone PO or IV on days 1, 8, 15 and 22. Patients 75 years or over may receive dexamethasone PO or IV on days 1, 2, 8, 9, 15, 16, 22 and 23. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Nebraska Medical Center

Principal Investigator
Muhamed Baljevic

Trial IDs

Primary ID 434-17
Secondary IDs NCI-2017-02024
Clinicaltrials.gov ID NCT03201250