Cyclophosphamide, Carfilzomib, Thalidomide, and Dexamethasone in Treating Patients With Newly Diagnosed Active Multiple Myeloma

A Phase I/II Trial of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients With Newly Diagnosed Active Multiple Myeloma

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Thalidomide may stop the growth of cancer cells by blocking blood flow to the tumor. Giving combination chemotherapy together with carfilzomib and thalidomide may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of carfilzomib when given together with cyclophosphamide, thalidomide, and dexamethasone in treating patients with newly diagnosed active multiple myeloma.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma
• Intervention / Treatment: Drug: carfilzomib; Drug: dexamethasone; Drug: thalidomide; Drug: cyclophosphamide

Detailed Description

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. (Phase I) II. In newly diagnosed myeloma to evaluate the response rate (CR, nCR, and VGPR) to carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone after four 28 day cycles. (Phase II)

SECONDARY OBJECTIVES:

I. Determine the overall response rate (CR, nCR, PR) after 4, 8, 12 cycles. II. Determine the duration of progression-free and overall survival for patients receiving this regimen.

III. To evaluate the incidence of toxicities for this regimen. IV. To evaluate the ability to successfully collect peripheral blood stem cells following four months of combination therapy.

OUTLINE: This is a phase I, dose escalation study of carfilzomib followed by a phase II study.

Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 3 months, then every 3 months for 1 year, and then every 6 months for up to 3 years.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • South Carolina
    • Charleston, South Carolina, United States, 29425-6350
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion

• Creatinine =< 2 mg/dL
• Calculated Creatinine Clearance >= 30 mL/min
• Total Bilirubin =< 2.0 mg/dL
• Alkaline Phosphatase =< 3 x ULN
• ALT =< 3 x ULN
• Absolute neutrophil count >= 1000/uL
• Platelet >= 75000/uL
• Hemoglobin >= 8.0 g/dL
• Untreated symptomatic myeloma: Prior non-systemic therapy for the treatment of solitary plasmacytoma is permitted, but >= 1 month should have elapsed from the last day of radiation; prior therapy with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is permitted; any additional agents not listed must be approved by the Principal Investigator
• Prior high dose corticosteroid therapy for twelve days (480 mg total dose) or less is permitted for emergent complications from newly diagnosed multiple myeloma
• Measurable disease of multiple myeloma, as defined by at least ONE of the following:
• Serum monoclonal protein >= 1.0 g by protein electrophoresis
• OR > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
• OR serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio; OR monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)
• ECOG performance status (PS) 0, 1, 2; ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator
• Willingness and able to provide informed written consent
• Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
• Willingness to return to Mayo Clinic enrolling institution for follow-up

Exclusion

• MGUS or smoldering myeloma
• Peripheral sensory neuropathy >= Grade 2 as defined by CTEP Active Version of the CTCAE
• Active malignancy with the exception of non melanoma skin cancer or in situ cervical or breast cancer
• Pregnant women or women of reproductive ability who are unwilling to use effective contraception
• Nursing women
• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment
• Known hypersensitivity, allergy or inability to tolerate any of the agents employed
• Active, uncontrolled infection
• Severe cardiac comorbidity
• New York Heart Association Class III or IV Heart Failure
• Recent history of myocardial infarction in the six months prior to registration
• Uncontrolled angina or electrocardiographic evidence of acute ischemia
• Severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of active conduction system abnormalities
• Cardiac amyloidosis with hypotension (systolic BP less than 100 mmHg)
• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
• The following medications are not permitted during the trial: any other investigational treatment; any cytotoxic chemotherapy; any other systemic anti-neoplastic therapy including, but not limited to, immunotherapy, hormonal therapy, or monoclonal antibody therapy
• Palliative radiation therapy is permitted if clinically indicated and not indicative of progressive disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm I; Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.	Drug: carfilzomib; Given IV; Other Names: PR-171; Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Decaspray; Drug: thalidomide; Given orally; Other Names: Kevadon; Synovir; THAL; Thalomid; Contergan; alpha-phthalimidoglutarimide; Drug: cyclophosphamide; Given orally; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Enduxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (Phase I)	To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse event attributed (definitely, probably, possibly) in the first or second cycle for patients enrolled to Dose Levels -1 and 0 and in the first cycle only for patients enrolled to Dose Levels 1 and 2. We are reporting the number of DLTs	From baseline to end of active treatment, up to 12 28-day cycles.
Percentage of Patients Who Have at Least a Confirmed Very Good Partial Response (Phase II)	The proportion of patients who have at least a confirmed very good partial response will be calculated by taking the number of patients with a very good partial response or a complete response divided by the total number of patients. A complete response is defined as: Negative immunofixation of the serum and urine; If at on study, only the measurable non-bone marrow parameter was FLC, normalization of FLC ratio; < 5% plasma cells in bone marrow; Disappearance of any soft tissue plasmacytomas A very good partial response is defined as: Serum and urine M-component detectable by immunofixation but not on electrophoresis or; If at on study, serum measurable, ≥ 90% or greater reduction in serum Mcomponent; Urine M-component <100 mg per 24 hour	Following the first 4 cycles of treatment (28 day cycles)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (Phase II)	PFS was defined as the time from registration to progression or death due to any cause. Progression was defined as any one or more of the following: • Increase of 25% from lowest confirmed response in: Serum M-component (absolute increase must be ≥ 0.5 g/dl)c Urine M-component (absolute increase must be ≥ 200 mg/24 hour) If at on study, only the measurable non-bone marrow parameter was FLC, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl) Bone marrow plasma cell percentage (absolute % must be 10%)d Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg/dl) that can be attributed solely to the plasma cell proliferative disorder	From baseline to progression or death up to 3 years
Time to Treatment Failure	The time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they were removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier	From baseline to end of active treatment
Stem Cell Collection and Engraftment (Phase II)	For patients going on to stem cell collection, the total number of CD34 positive cells collected per collection, days to platelets over 20,000 without transfusion and ANC over 1000 will be recorded. If a patient fails to collect adequate stem cells for transplant, this will be recorded as such. The number of patients with successful stem cell mobilization are reported.	Following the first 4 courses of treatment
Complete Response (Phase II)	In patients continuing beyond 4 cycles the ability to induce complete response will be evaluated at completion of planned therapy.	Following the first 4 courses of treatment
Survival Time (Phase II)	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier	From baseline to death
Progression Free Survival (12 Month)	Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 12 month mark.	12 months
Progession Free Survival (24 Month)	Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 24 month mark.	24 months
Overall Survival (12 Month)	12 Month Overall survival is defined as the proportion of patients to still be alive after 12 months.	From baseline to death
Overall Survival (24 Month)	24 Month Overall survival is defined as the proportion of patients to still be alive after 24 months.	From baseline to death

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Study Chair: Joseph R. Mikhael, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): September 5, 2017

Study Registration Dates

• First Submitted: January 26, 2010
• First Submitted That Met QC Criteria: January 26, 2010
• First Posted (ESTIMATE): January 27, 2010

Study Record Updates

• Last Update Posted (ACTUAL): December 12, 2017
• Last Update Submitted That Met QC Criteria: November 14, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Dexamethasone; Cyclophosphamide; Thalidomide
• Other Study ID Numbers: MC0982 (OTHER: Mayo Clinic Cancer Center); NCI-2009-01699 (REGISTRY: NCI-CTRP); PT-171-502 (OTHER: Onyx Protocol); 09-004091 (OTHER: Mayo Clinic IRB)