A Multicenter Phase 1/2b Study of the Bruton[Single Quote]s Tyrosine Kinase Inhibitor, Ibrutinib (PCI-32765), in Combination with Carfilzomib (Kyprolis(TM)) in Subjects with Relapsed or Relapsed and Refractory Multiple Myeloma
- Zale Lipshy University Hospital
This Phase 1 study is an open-label study. The Dose escalation portion of the study is designed to establish the MTD and toxicity profile of ibrutinib in combination with carfilzomib. up to three cohorts may be explored and dose escalation will follow the 3+3 dose escalation schema. in Dose expansion, a maximum of two cohorts will be expanded up to a total of 18 subjects per cohort in the absence of dose-limiting toxicity (DLT) to ensure a more accurate assessment of the initial toxicity and efficacy profile.
approximately 42 subjects will be enrolled in this Phase 1 study. Which include a Screening Phase, Treatment Phase and a Follow-up Phase. The Screening Phase assessments will be performed within 28 days prior to study treatment. eligible subjects must have diagnosis of MM that meets published diagnostic criteria, have received at least two prior lines of therapy including BTZ and an iMiD, and have documented relapse/refractory disease according to iMWG consensus criteria. The Treatment Phase will extend from first dose until criteria for permanent discontinuation of ibrutinib are met.
During the Treatment Phase, efficacy evaluations will be performed at the beginning of each cycle and will include an overall disease assessment, complete blood count (CBC), and physical examination.
The Post-treatment Follow-up Phase will begin once a subject discontinues ibrutinib treatment and will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first.
* Subjects who discontinue for reasons other than disease progression (ie, for adverse event
or investigator decision), will complete an end of Treatment Visit (30 (+-) 3 days from the last dose of ibrutinib or carfilzomib, whichever is later), and should continue to have disease evaluations (12 weeks (+-) 14 days) until disease progression.
* Subjects who discontinue due to disease progression will complete an end of Treatment Visit and be followed for survival and subsequent anti-cancer therapy (12 weeks (+-) 14 days) until study ends.
it is imperative that survival status be assessed and that the date of death is documented for each subject that has died.
1. Subjects with MM who have received at least two prior lines of therapy (Appendix 5) including BTZ and an IMiD and had either no response or documented disease progression to the most recent treatment regimen.
2. Measurable disease is defined by at least ONE of the following:
* Serum monoclonal protein (SPEP) >=1 g/dL
* >=200 mg of monoclonal protein in the urine on 24 hour electrophoresis (UPEP)
* Serum free light chain (sFLC): involved FLC >=10 mg/dL (>=100 mg/L) AND abnormal kappa to lambda serum free light chain ratio Ibrutinib (PCI-32765)
3. Adequate hematologic function within 7 days prior to enrollment (Phase 1), defined as:
* Absolute neutrophil count (ANC) >=750/mm3
* Platelet counts >=75,000/mm3 (or >=50,000/mm3 if bone marrow involvement is >=50%)
* Hemoglobin level >=8 g/dL Results must be independent of transfusion and growth factor support for at least 7 days, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which requires at least 14 days.
4. Adequate hepatic and renal function within 7 days prior to enrollment (Phase 1):
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3 x upper limit of normal (ULN)
* Total bilirubin <=1.5 x ULN (unless bilirubin rise is due to Gilbert[Single Quote]s syndrome or of non-hepatic origin)
* Estimated Creatinine Clearance (Cockcroft-Gault) >=30 mL/min
5. Men and women >= 18 years of age on the day of signing the informed consent.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0x2.
7. Female subject of childbearing potential must have a negative serum (human chorionic gonadotropin) or urine pregnancy test within 3 days prior to enrollment (Phase 1) and agree to use dual methods of contraception during the study and for 1 month following the last dose with ibrutinib. Post menopausal females (>45 years old and without menses for >1 year) and surgically sterilized females are exempt from this criterion.
8. Male subject must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.
9. Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
10. Willing to provide blood and tissue samples for correlative research purposes (Phase 1).