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

Exclusion Criteria

• •* Absence of history of congenital long QT syndrome
• •13. Patients who have received radiation therapy (RT) must have completed this at least 4 weeks prior to starting therapy with cabozantinib, with the following exceptions:
• •* Local RT to enhance bone healing of a pathologic fracture within 2 weeks prior to starting cabozantinib
• •* Local RT for post-fracture pain that is refractory to analgesics within 2 weeks prior to starting cabozantinib
• •14. Patients who have undergone any recent major surgery within 4 weeks prior to starting therapy with cabozantinib, with the following exceptions:
• •* Vertebroplasty and/or kyphoplasty must have been within 1 week prior to starting cabozantinib
• •* Planned elective surgery unrelated to the patient's diagnosis of MM, such as hernia repair, may be allowed, at the discretion of the principle investigator, as long as it was performed within 2 weeks prior to starting cabozantinib, and patients have recovered fully.
• •15. 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 mm3 will be eligible (HIV positive patients on combination antiretroviral therapy will be ineligible)
• •16. 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)
• •17. 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 (bHCG) or urine pregnancy before the first dose of cabozantinib or carfilzomib.
• •18. 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.
• •1. 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.
• •2. Patients who have known CNS involvement with MM
• •3. 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.
• •4. Patients with a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib.
• •5. 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.
• •6. 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.
• •7. Pregnant or lactating women
• •8. 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
• •9. Patients who have required plasmapheresis and exchange less than 2 weeks prior to initiation of therapy with cabozantinib
• •10. Patients with known moderate or severe hepatic impairment, active hepatitis A, B, and/or C infection
• •11. 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.
• •12. Allergy to carfilzomib or cabozantinib or any excipients
• •13. 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.
• •14. The subject has experienced any of the following:
• •* clinically-significant GI bleeding within 6 months before the first dose of study treatment;
• •* 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,
• •* hemoptysis of ≥ 0.5 teaspoon (2.5 ml) 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.
• •15. The subject has radiographic evidence of cavitating pulmonary lesion(s);
• •16. The subject has tumor invading or encasing any major blood vessels;
• •17. 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;
• •18. QTcF \> 500 msec within 1 month before the first dose of study treatment:
• •\- Three ECGs 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.
• •19. Inability to swallow intact tablets
• •20. The subject has PT/INR or PTT test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment;
• •21. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel);
• •22. Subjects who have Carfilzomib-related posterior reversible encephalopathy syndrome (PRES) and thrombotic microangiopathy (TMA) should not be challenged with Carfilzomib.