Pomalidomide in Combination With High Dose Dexamethasone and Oral Cyclophosphamide

NCT01432600 | Completed Phase 1 Results DMC

• 2 other identifiers: MCC-16705PO-MM-PI-0039
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 3

Brief Summary

The main purpose of this study is to see whether pomalidomide can help people with myeloma. Researchers also want to find out if pomalidomide is safe and tolerable.

Conditions

Myeloma

Keywords

Multiple Myeloma; Relapsed; Refractory; Corticosteroids

Outcome Measures

Primary Outcomes (2)

• Phase I - Maximum Tolerated Dose (MTD)

  The maximum tolerated dose of oral weekly cyclophosphamide in milligrams (mg), in combination with pomalidomide and dexamethasone. Dose Escalation of Cyclophosphamide, orallly (PO) days 1, 8, 15 as follows: Level 1: 300 mg; Level 2: 400 mg; Level 3: 500 mg. The period for assessment of Dose Limiting Toxicity (DLT) is the first cycle (28 days). The following toxicities will be considered dose limiting if encountered only in the phase I portion of the study: Febrile neutropenia; Grade 3 or 4 non-hematologic toxicity related to treatment with pomalidomide or cyclophosphamide; Participants must have received optimal symptomatic treatment for Grade 3 or 4 nausea, vomiting, or diarrhea to be considered a DLT; Grade 4 transaminitis; Grade 3 transaminitis must be present for ≥ 7 days to be considered a DLT; Grade 4 thrombocytopenia for 7 or more days; Grade 4 neutropenia for 7 or more days.

  28 Days

• Phase II - Overall Response Rate (ORR)

  Overall response, Minimal Remission (MR) or better per treatment arm, using the uniform response criteria by the International Myeloma Working Group (IMWG) of pomalidomide in combination with high dose dexamethasone with or without cyclophosphamide in participants with relapsed and refractory myeloma. In addition, Minimal response was incorporated in those response criteria as this is a valid endpoint in patients with relapsed or refractory myeloma. MR: 25-49% reduction in serum paraprotein and a 50-89% reduction in urine light chain excretion; A 25-49% reduction in the size of soft tissue plasmacytoma must be demonstrated is applicable.

  36 Months

Secondary Outcomes (3)

• Phase II - Median Progression Free Survival (PFS)

  36 Months

• Phase II - Median Overall Survival (OS)

  36 Months

• Phase II - Occurrence of Possibly Related Adverse Events (AEs)

  Up to 48 Months

Study Arms (4)

A: Dose Escalation of Cyclophosphamide

EXPERIMENTAL

Phase I: Pomalidomide, high dose dexamethasone and oral cyclophosphamide: Pomalidomide 4 mg by mouth (PO) days 1-21 of a 28 days cycle. Dexamethasone 40\* mg PO days 1- 4, 15-18 of a 28 days cycle for the first 4 cycles and subsequently 40 mg PO Days 1,8,15, 22. \*Participants who were \>75 years of age or those who were known to be intolerant to 40 mg weekly dexamethasone received 20 mg dexamethasone on the same schedule. Dose Escalation of Cyclophosphamide, orallly (PO) days 1, 8, 15 as follows: Level 1: 300 mg; Level 2: 400 mg; Level 3: 500 mg. Aspirin 81 mg PO daily (unless the participants had contraindications or were receiving other form of anticoagulation for other indications).

Drug: Pomalidomide; Drug: Dexamethasone; Drug: Cyclophosphamide

B: Pomalidomide and Dexamethasone

ACTIVE COMPARATOR

Randomized Phase II - Pomalidomide high dose dexamethasone: Pomalidomide 4 mg PO days 1-21 of a 28 days cycle. Dexamethasone 40\* mg PO Days 1,8,15, 22. \*Participants who were \>75 years of age or those who were known to be intolerant to 40 mg weekly dexamethasone received 20 mg dexamethasone on the same schedule. Aspirin 81 mg PO daily (unless the participants had contraindications or were receiving other form of anticoagulation for other indications).

Drug: Pomalidomide; Drug: Dexamethasone

C: Pomalidomide/Dexamethasone/Cyclophosphamide

ACTIVE COMPARATOR

Randomized Phase II - Pomalidomide high dose dexamethasone and oral cyclophosphamide: Pomalidomide 4 mg PO days 1-21 of a 28 days cycle. Dexamethasone 40\* mg PO days 1- 4, 15-18 of a 28 days cycle for the first 4 cycles and subsequently 40 mg PO Days 1,8,15, 22. \*Participants who were \>75 years of age or those who were known to be intolerant to 40 mg weekly dexamethasone received 20 mg dexamethasone on the same schedule. Cyclophosphamide 400 mg PO days 1, 8, 15. Aspirin 81 mg PO daily (unless the participants had contraindications or were receiving other form of anticoagulation for other indications).

Drug: Pomalidomide; Drug: Dexamethasone; Drug: Cyclophosphamide

D: Crossover

OTHER

Crossover from Arm B to Arm D. Participants who experienced progressive disease in arm B were allowed to crossover to arm D at the discretion of the treating physician, in which case oral weekly Cyclophosphamide (400 mg orally on days 1, 8, and 15) was added to their tolerated dose of pomalidomide and dexamethasone.

Drug: Pomalidomide; Drug: Dexamethasone; Drug: Cyclophosphamide

Interventions

Pomalidomide DRUG

Pomalidomide at 4 mg by mouth (PO) as outlined in the treatment arms.

Also known as: CC-4047, POMALYST®

A: Dose Escalation of Cyclophosphamide; B: Pomalidomide and Dexamethasone; C: Pomalidomide/Dexamethasone/Cyclophosphamide; D: Crossover

Dexamethasone DRUG

Dexamethasone at 40 mg (20 mg) PO as outlined in the treatment arms.

Also known as: Decadron®

A: Dose Escalation of Cyclophosphamide; B: Pomalidomide and Dexamethasone; C: Pomalidomide/Dexamethasone/Cyclophosphamide; D: Crossover

Cyclophosphamide DRUG

The dose escalation uses a standard "3x3" design: Ex: If none of the first 3 participants have a DLT, enter 3 participants at the next higher dose level. Once the maximum tolerated dose (MTD) of oral weekly cyclophosphamide in combination with pomalidomide and dexamethasone was determined, investigators proceeded with the second phase of the trial, a randomized phase II study comparing pomalidomide and dexamethasone with pomalidomide, dexamethasone and oral weekly cyclophosphamide delivered at the MTD determined in the phase I study.

Also known as: Cytoxan

A: Dose Escalation of Cyclophosphamide; C: Pomalidomide/Dexamethasone/Cyclophosphamide; D: Crossover

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have relapsed or refractory multiple myeloma. Refractory disease is defined as patients who experience disease progression on active therapy or within 60 days after the discontinuation of therapy. Relapsed disease is defined as achievement of at least a partial response followed by disease progression after 60 days of discontinuing active therapy.
• Must have measurable disease as assessed by one of the following criteria: Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis; \>200 mg of monoclonal protein in the urine on 24 hour electrophoresis; Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
• Must have received at least 2 prior therapies to include prior immunomodulatory drug (lenalidomide) and the patient must be refractory to lenalidomide (defined as progressive disease during active therapy or within 60 days of discontinuation of therapy). All previous cancer chemotherapy (bisphosphonates are not included), including surgery, must have been discontinued ≥2 weeks prior to first dose of study drug. Prior radiotherapy must have been completed \> 2 weeks prior to the start of study drug unless the radiation field would not impact marrow reserve in the opinion of the investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%
• Must have acceptable organ function: total bilirubin less than 1.5 mg/dL; aspartic transaminase (AST)/alanine transaminase (ALT) ≤2.5 X institutional upper limit of normal (ULN); serum creatinine \< 3mg/dL
• Must have adequate hematologic function as evidenced by the following:
• For the Phase I study: Absolute neutrophil count (ANC) ≥ 1000 per mm³; Platelet count ≥ 50,000 per mm³.
• For the Phase II portion, patients with greater than 50% bone marrow plasmacytosis will be allowed to enter the trial if the platelet count is greater than 30,000 per mm³ and regardless of baseline absolute neutrophil count if it is felt to be related to active myeloma and if in the opinion of the investigator, growth factor support can result in improvement in the neutrophil count to greater than 1000 per mm³ (growth factor can be used during screening).
• Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting 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 vasectomy.
• Ability to understand and the willingness to sign a written informed consent document
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin).
• All study participants must be registered into the mandatory POMALYST REMS™ program, and be willing and able to comply with the requirements of the POMALYST REMS™ program.

You may not qualify if:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form
• Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Use of any other experimental drug or therapy within 28 days of baseline.
• Known hypersensitivity to thalidomide or lenalidomide
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, pomalidomide or similar drugs
• Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C
• May not be receiving any other investigational agents
• Pregnant or breast feeding females (Lactating females must agree not to breast feed while taking pomalidomide).
• Patients with prior pomalidomide therapy (greater than 1 cycle) are excluded.
• Another active malignancy requiring treatment within the next 12 months, with the exception of basal cell skin cancer, in situ cervical cancer, in situ breast cancer and asymptomatic prostate cancer
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (except simple urinary tract or upper respiratory tract infection), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Inability to comply with the protocol requirements or participation in any other clinical study
• Corticosteroid therapies of \>20 mg/day prednisone, \>4 mg/day dexamethasone, \>80 mg/day hydrocortisone, or equivalent
• Allogeneic stem cell/bone marrow transplant within 12 months of first dose of study drug or active graft versus host disease
• Patients with existing peripheral neuropathy grade \>2

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Celgene: collaborator

Study Sites (3)

University of California San Francisco

San Francisco, California, 94143, United States

Location

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Mount Sinai School of Medicine, The Tisch Cancer Institute

New York, New York, 10029-6574, United States

Location

Related Publications (1)

• Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. doi: 10.1182/blood-2015-11-682518. Epub 2016 Mar 1.

  PMID: 26932802 DERIVED

MeSH Terms

Conditions

Neoplasms, Plasma Cell; Multiple Myeloma; Recurrence

Interventions

pomalidomide; Dexamethasone; Calcium Dobesilate; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Limitations and Caveats

Phase 2 nature of design may have limited power to detect statistically significant differences in some efficacy outcomes and toxicity measures.

Results Point of Contact

• Title: Dr. Rachid Baz
• Organization: H. Lee Moffitt Cancer Center and Research Institute

rachid.baz@moffitt.org

813-745-8212

Study Officials

• Rachid Baz, M.D.

  H. Lee Moffitt Cancer and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2011
• First Posted: September 13, 2011
• Study Start: November 1, 2011
• Primary Completion: August 1, 2016
• Study Completion: August 1, 2016
• Last Updated: May 23, 2017
• Results First Posted: May 23, 2017

Record last verified: 2017-02

Locations

US (3)