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Carfilzomib, Pomalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

Information source: University of Chicago
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Multiple Myeloma

Intervention: pomalidomide (Drug); carfilzomib (Drug); dexamethasone (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: University of Chicago

Official(s) and/or principal investigator(s):
Andrzej Jakubowiak, Principal Investigator, Affiliation: University of Chicago Comprehensive Cancer Center

Summary

This phase I/II trial studies the safety and the best dose of carfilzomib and to see how well it works when given together with pomalidomide and dexamethasone in treating patients with relapsed or refractory multiple myeloma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Pomalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving carfilzomib together with pomalidomide and dexamethasone may kill more cancer cells

Clinical Details

Official title: Multicenter, Open-label, Single-arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment With Pomalidomide, Dexamethasone, and Carfilzomib (PdC) in Subjects With Relapsed and Relapsed/Refractory Multiple Myeloma

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

MTD of carfilzomib when administered in combination with fixed dosing pomalidomide and dexamethasone

Partial response rate after 4 courses according to IMW criteria

Secondary outcome:

Overall response rate

Time to progression

Duration of response

Progression-free survival

Overall survival

Detailed description: PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) of carfilzomib when administered in combination with fixed dosing pomalidomide and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma. II. To determine the efficacy of the combination regimen at the MTD as measured by partial response (PR) response rate defined as per International Myeloma Working Group (IMW) criteria. SECONDARY OBJECTIVES: I. To determine the best stringent complete response (sCR)/CR/nodular complete response (nCR) and >= very good partial response (VGPR) rates. II. To estimate the time on study (TOS), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) distributions. III. To further define the toxicity at the MTD. TERTIARY OBJECTIVES: I. To perform an analysis of a subset of patients who are refractory to either pomalidomide or carfilzomib or lenalidomide, bortezomib, and dexamethasone (RVD) combination. II. To evaluate the status of minimal residual disease (MRD) in patient who achieve sCR, CR or nCR. III. To evaluate prognostic markers and markers of response to pomalidomide, dexamethasone, and carfilzomib (PdC) in patients refractory to lenalidomide by analyzing pre-treatment clinical covariates and pre-treatment plasma cell profiles by proteomics and gene expression profiling (GEP). OUTLINE: This is a phase I dose-escalation study of carfilzomib followed by phase II. Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15 and 16, pomalidomide orally (PO) once daily (QD) on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Treatment repeats every 28 days for at least 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease may continue to receive treatment in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 28 days and then every 3 months for up to 2 years.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Relapsed and relapsed/refractory multiple myeloma requiring systemic therapy

- All patients must have failed 1+ prior treatment, one of which must include

lenalidomide therapy and have been determined to be refractory to it

- Refractory to lenalidomide will be defined as a history of progression on or

within 60 days of completion of a regimen of a minimum of 2 cycles containing full or maximally tolerated dose of lenalidomide

- Progressing on lenalidomide maintenance will be allowed provided that the trial

of at least 2 months of lenalidomide at 25 mg or maximum tolerated dose was given to meet the lenalidomide refractory status

- In addition to lenalidomide refractory, patients refractory to (1) pomalidomide

(2) carfilzomib, or (3) RVD are permitted limited to separate cohorts enrollment

- Measurable disease, as indicated by one or more of the following:

- Serum M-protein >= 0. 5 g/dL

- Urine M-protein >= 200 mg/24 hours

- If serum protein electrophoresis is felt to be unreliable for routine M-protein

measurement, then quantitative immunoglobulin levels are acceptable

- Life expectancy of more than 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Bilirubin < 1. 5 times the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2. 5 times ULN

- Absolute neutrophil count (ANC) >= 1. 0 x 10^9/L

- Hemoglobin >= 8 g/dL

- Platelet count >= 75 x 10^9/L; subjects may receive red blood cells (RBC)

transfusions or platelet transfusions, if clinically indicated in accordance with institutional guidelines; however, screening platelet count should be independent of platelet transfusions for at least 2 weeks

- Calculated or measured creatinine clearance of >= 30 mL/minute

- Written informed consent in accordance with federal, local, and institutional

guidelines

- Females of childbearing potential (FCBP) must have a negative serum or urine

pregnancy test with a sensitivity of at least 25mIU/mL within 10-14 days and again within 24 hours prior to starting course 1 of pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

- Subjects must agree to adhere to all study requirements, visit schedule, outpatient

treatment, required concomitant medications, and laboratory monitoring Exclusion Criteria:

- Non-secretory or hyposecretory multiple myeloma, defined as < 0. 5 g/dL M-protein in

serum, < 200 mg/24 hr urine M-protein, or disease only measured by serum free light chain

- Patients for whom there is the prospect of stem cell transplantation in the next 6

months in the treatment plan are excluded (including patients for whom the PdC regimen is being considered as pre-transplant cytoreduction)

- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and

skin changes)

- Plasma cell leukemia

- Waldenström's macroglobulinemia or immunoglobulin M (IgM) myeloma

- Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of

protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)

- Participation in an investigational therapeutic study within 3 weeks or within 5 drug

half lives (t1/2) prior to first dose, whichever time is greater

- Refractory to bortezomib, except if meeting criteria for RVD-refractory cohort

- Pregnant or lactating females

- History of allergy to mannitol or prior hypersensitivity to thalidomide, lenalidomide

or pomalidomide

- Major surgery within 3 weeks prior to first dose, prior peripheral stem cell

transplant within 12 weeks of study enrollment, subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT], or any investigational therapy) within 21 days of enrollment

- Myocardial infarction within 6 months prior to enrollment, New York Heart Associate

(NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

- Uncontrolled hypertension or diabetes

- Acute active infection requiring systemic antibiotics, antivirals, or anti fungals

within two weeks prior to first dose

- Known or suspected human immunodeficiency (HIV) infection, known HIV seropositivity

- Active hepatitis A, B, or C infection

- Non-hematologic malignancy within the past 3 years except adequately treated basal

cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix or breast, prostate cancer < Gleason grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone

- Any clinically significant medical disease or condition that, in the investigator's

opinion, may interfere with protocol adherence or a subject's ability to give informed consent

- Significant neuropathy (grades 3-4, or grade 2 with pain) at the time of the first

dose and/or within 14 days before enrollment

- Contraindication to any of the required concomitant drugs, including proton-pump

inhibitor (eg, lansoprazole), enteric-coated aspirin, allopurinol or if a history of prior thrombotic disease, warfarin or low molecular weight heparin

- Subjects in whom the required program of PO and IV fluid hydration is

contraindicated, eg, due to pre-existing pulmonary, cardiac, or renal impairment

- Subjects with known or suspected amyloidosis of any organ

- Subjects with pleural effusions requiring thoracentesis or ascites requiring

paracentesis

Locations and Contacts

University of Chicago Comprehensive Cancer Center, Chicago, Illinois 60637-1470, United States; Recruiting
Andrzej J. Jakubowiak, Phone: 773-834-1592, Email: ajakubowiak@medicine.bsd.uchicago.edu
Andrzej J. Jakubowiak, Principal Investigator

Hackensack University Medical Center, Hackensack, New Jersey 07601, United States; Not yet recruiting
David S. Siegel, Phone: 201-336-8704, Email: dsiegel@humed.com
David S. Siegel, Principal Investigator

Additional Information

Starting date: August 2012
Last updated: June 22, 2015

Page last updated: August 23, 2015

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