Carfilzomib With Bendamustine and Dexamethasone in Multiple Myeloma

Phase I/II Study of Carfilzomib in Combination With Bendamustine and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

This study is designed to define dose-limiting toxicity and determine preliminary evidence of efficacy of carfilzomib (CFZ) in combination with bendamustine and dexamethasone for patients with newly diagnosed multiple myeloma (MM).

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Bendamustine; Drug: Carfilzomib; Drug: Dexamethasone

Detailed Description

Multiple myeloma (MM) is a malignant plasma cell disorder resulting in approximately 11,000 deaths in the United States each year. It is estimated that between 60,000-80,000 people are currently under treatment for refractory or relapsed MM. Prognosis and survival have improved over the last 20 years, but the disease is still universally fatal despite efforts to develop new and more effective chemotherapeutic regimens. Therefore, new regimens need to be developed for patients prior to peripheral blood stem cell transplant and for those unable to tolerate the toxicity of transplant.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

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 Criteria:

1. Age ≥ 18 years.
2. Life expectancy ≥ 3 months.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
4. Adequate hepatic function.
5. Sufficient Absolute neutrophil count (ANC) within 14 days prior to randomization.
6. Sufficient Hemoglobin within 14 days prior to randomization (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines).
7. Sufficient platelet count 14 days prior to randomization.
8. Creatinine Clearance ≥ 30 mL/minute within 7 days prior to randomization.
9. Left Ventricular Ejection Fraction ≥ 40%.
10. Written informed consent in accordance with federal, local, and institutional guidelines.
11. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception.
12. Male subjects must agree to practice contraception.
13. Patients must have histologically or cytologically confirmed symptomatic multiple myeloma (MM). Patients should not have previously been treated.
14. Prior kyphoplasty, vertebroplasty, local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture) are permitted.
15. Patients are allowed up to two cycles of high dose steroids if needed for symptomatic disease before study enrollment.

Exclusion Criteria:

1. Patients who have had chemotherapy for Multiple Myeloma. Exception: local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture).
2. Patients currently receiving high dose systemic steroids for treatment of Multiple Myeloma in excess of 320mg total dose of dexamethasone or equivalent, patients who received an investigational agent within 5 half-lives of the agent.
3. Patients with non-measurable Multiple Myeloma or primary plasma cell leukemia.
4. Pregnant or lactating females.
5. Major surgery within 21 days prior to enrollment.
6. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to enrollment.
7. Known human immunodeficiency virus (HIV) infection.
8. Known active hepatitis B or C infection.
9. Unstable angina or myocardial infarction within 4 months prior to enrollment.
10. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment.
11. Uncontrolled, non-hematologic malignancy requiring active treatment.
12. Patients with known brain metastases (treated or not) will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
13. Significant neuropathy within 14 days prior to randomization.
14. Known history of allergy to Captisol, or to other agents in the study.
15. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
16. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment.
17. Any other 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CFZ with bendamustine and dexamethasone; Subjects will receive Carfilzomib on Days 1, 2, 8, 9, 15, and 16 every 28 days with dose escalation from 27, 36, 45 to 56 mg/ m2 . No matter what target dose the subject will receive, days 1 and 2 doses in the first cycle will always be 20 mg/m2, followed by target dose for all subsequent dates and cycles. Bendamustine will be given IV on days 1 and 2 with dose escalation up to 90 mg/m2 and dexamethasone 20 mg orally or intravenously on 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle. Study treatment will be given until 8 cycles of treatment are completed or until disease progression, whichever comes first.

Drug: Bendamustine; Bendamustine will be administered IV on days 1 and 2 with dose escalation up to 90 mg/m2 of each 28-day cycle. Dose escalation is as follows: -1 | 60 mg/m2; | 70 mg/m2; | 70 mg/m2; | 90 mg/m2; | 90mg/m2; | 90 mg/m2; Other Names: Treanda; Drug: Carfilzomib; Carfilzomib will be administered IV on Days 1, 2, 8, 9, 15, and 16 every 28 days. Dose Escalation is as follows: -1 | 27 mg/m2; | 27 mg/m2; | 36 mg/m2; | 36 mg/m2; | 45 mg/m2; | 56 mg/m2; Other Names: Kyprolis; CFZ; Drug: Dexamethasone; Dexamethasone will be administered PO or IV, 20 mg, on 1, 2, 8, 9, 15, 16 and 22, 23 of each 28-day cycle.; Other Names: Decadron; Dexamethasone Intensol; Dexpak Taperpak

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of Carfilzomib in combination with bendamustine and dexamethasone	The primary endpoint of this study is dose-limiting toxicity (DLT), to define the recommended phase II dose.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	Includes complete response and partial response.	2 years
Duration of response (DOR)	The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the study treatment started).	2 years
Progression free survival (PFS)	PFS is defined as the duration of time from start of study treatment to time of progression or death, whichever occurs first.	2 years
Time to best response	Time to the best response recorded.	2 years
Overall survival (OS) rate	The percentage of people who are still alive.	2 years
Number of adverse events (AEs)	Total number of AEs observed.	2 years
Number of adverse events in relation to carfilzomib maintenance	Total number of AEs observed that are determined to be related to carfilzomib.	2 years

Collaborators and Investigators

• Sponsor: Siyang Leng
• Investigators: Principal Investigator: Siyang Leng, MD, Columbia University

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: December 2, 2013
• First Submitted That Met QC Criteria: December 5, 2013
• First Posted (Estimate): December 6, 2013

Study Record Updates

• Last Update Posted (Actual): June 14, 2019
• Last Update Submitted That Met QC Criteria: June 12, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: transplant; phase I; phase II; dexamethasone; Newly diagnosed; multiple myeloma; dose escalation; Treanda; myeloma; bendamustine; carfilzomib; Kyprolis; non-transplant; plasma cell
• 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; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Bendamustine Hydrochloride
• Other Study ID Numbers: AAAJ2359

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No