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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

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


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)


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.


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

After completion of study treatment, patients are followed up at 28 days and then every 3
months for up to 2 years.

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

- 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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

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

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Andrzej Jakubowiak

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

December 2015

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



Hackensack University Medical Center Hackensack, New Jersey  07601
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470