Carfilzomib, Pegylated Liposomal Doxorubicin Hydrochloride, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

NCT01246063 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 201102043
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this phase I/II trial is to determine the maximal tolerated dose (MTD) of carfilzomib together with pegylated liposomal doxorubicin hydrochloride (PLD) with or without dexamethasone, and then to establish the efficacy and safety of this novel combination in patients with relapsed or refractory multiple myeloma

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (5)

• Maximum Tolerated Dose (MTD) of Carfilzomib and Pegylated Liposomal Doxorubicin (Phase I - Part 1).

  * MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level. * Please note that the maximum tolerated dose of carfilzomib and pegylated liposomal doxorubicin was not reached. The data below is the recommended dosage for further studies.

  28 days (completion of first cycle of all Phase I - Part 1 patients)

• Maximum Tolerated Dose (MTD) of Carfilzomib and PLD (Phase I - Part 2).

  -MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.

  28 days (completion of first cycle of all Phase I - Part 2 patients)

• Maximum Tolerated Dose (MTD) of Dexamethasone (Phase I - Part 2).

  -MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.

  28 days (completion of first cycle of all Phase I - Part 2 patients)

• Phase 2 - Efficacy of Carfilzomib in Combination With PLD and Dexamethasone as Measured by the Percentage of Participants With Confirmed Tumor Responses

  -A confirmed response is defined to be a complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG Criteria.

  Completion of treatment (median number of cycles was 9.5 (range 1-34))

• Phase 2 - Toxicity of Carfilzomib in Combination With PLD and Dexamethasone as Measured by Number of Participants Who Experience Grade 3/4 Toxicity

  Through 30 days after completion of treatment (median number of cycles was 9.5 (range 1-34))

Secondary Outcomes (3)

• Median Overall Survival

  Completion of follow-up (median of 23.3 months)

• Progression-free Survival Time (Phase 2 Only)

  Through completion of follow-up (median follow-up was 23.3 months)

• Median Duration of Overall Response

  Through completion of follow-up (median follow-up was 23.3 months)

Study Arms (6)

Phase I - Part 1 Dose Level 0 (Carfilzomib 20/27 mg/m^2)

EXPERIMENTAL

Dose Level 0: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (27 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (27 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (27 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6.

Drug: carfilzomib; Drug: pegylated liposomal doxorubicin (PLD)

Phase I - Part 1 Dose Level 1 (Carfilzomib 20/36 mg/m^2)

EXPERIMENTAL

Dose Level 1: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (36 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (36 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (36 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6. Dose Level 1: Carfilzomib IV (1 dose level above MTD) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (1 dose level above MTD) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (1 dose level above MTD) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib. Dose Level 2: Carfilzomib IV (2 dose levels above MTD) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (2 dose levels above MTD) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (2 dose levels above MTD) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Drug: carfilzomib; Drug: pegylated liposomal doxorubicin (PLD)

Phase I - Part 1 Dose Level 2 (Carfilzomib 20/45 mg/m^2)

EXPERIMENTAL

Dose Level 2: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (45 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (45 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (45 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6.

Drug: carfilzomib; Drug: pegylated liposomal doxorubicin (PLD)

Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2)

EXPERIMENTAL

Dose Level 3: Carfilzomib IV (20 mg/m\^2) D1\&D2 of C1 and carfilzomib IV (56 mg/m\^2)D8, D9, D15, D16 of C1. Carfilzomib IV (56 mg/m\^2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (56 mg/m\^2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m\^2)D8 C1-6.

Drug: carfilzomib; Drug: pegylated liposomal doxorubicin (PLD)

Phase I -Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone)

EXPERIMENTAL

Cohort 0: Carfilzomib IV (56 mg/\^2 - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (56 mg/m\^2 - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (30 mg/m\^2 - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Drug: carfilzomib; Drug: pegylated liposomal doxorubicin (PLD); Drug: Dexamethasone

Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone)

EXPERIMENTAL

Carfilzomib IV (56 mg/\^2 - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (56 mg/m\^2 - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (30 mg/m\^2 - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Drug: carfilzomib; Drug: pegylated liposomal doxorubicin (PLD); Drug: Dexamethasone

Interventions

carfilzomib DRUG

Also known as: Kyprolis, CFZ

Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone); Phase I - Part 1 Dose Level 0 (Carfilzomib 20/27 mg/m^2); Phase I - Part 1 Dose Level 1 (Carfilzomib 20/36 mg/m^2); Phase I - Part 1 Dose Level 2 (Carfilzomib 20/45 mg/m^2); Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2); Phase I -Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone)

pegylated liposomal doxorubicin (PLD) DRUG

Also known as: DOXIL

Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone); Phase I - Part 1 Dose Level 0 (Carfilzomib 20/27 mg/m^2); Phase I - Part 1 Dose Level 1 (Carfilzomib 20/36 mg/m^2); Phase I - Part 1 Dose Level 2 (Carfilzomib 20/45 mg/m^2); Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2); Phase I -Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone)

Dexamethasone DRUG

Also known as: Decadron

Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone); Phase I -Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone)

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed diagnosis of multiple myeloma with a measurable disease parameter at time of screening; a measurable disease parameter is defined as one or more of the following:
• Serum monoclonal protein \>= 0.5 g/dl
• hour urine monoclonal protein \>= 0.2 g/24 hour
• Serum free light chain ratio \> 5 x normal ratio with an absolute difference of 10mg/dl between the involved and uninvolved free light chain
• Soft tissue plasmacytoma \>= 2 cm measurable by either physical examination and/or applicable radiographs (e.g. magnetic resonance imaging \[MRI\], computed tomography \[CT\], etc)
• Bone Marrow Plasma Cells \>= 30%
• Documentation of at least one line of prior myeloma therapy now with relapsed or refractory disease requiring re-treatment
• At least 18 years of age at the time of signing the informed consent.
• Performance status of Eastern Cooperative Oncology Group (ECOG) =\< 2 or Karnofsky \>= 60%; participants with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible
• Required laboratory values
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) and aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) \< 2.5 x the upper limit of the institutional normal value (ULN)
• Total bilirubin =\< 1.5 x upper limit of normal (ULN)
• Absolute neutrophil count (ANC) \>= 1,000
• Hemoglobin \>= 8 g/dl
• Platelets \>= 50,000

You may not qualify if:

• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma Cell Leukemia
• Waldenstrom's macroglobulinemia
• Pregnant or lactating females
• Use of any anti-myeloma drug therapy within 14 days of initiation of study drug treatment excluding corticosteroids if given for an indication other than myeloma; bisphosphonates are not considered anti-myeloma drugs
• Participation in an investigational therapeutic study within 14 days of initiation of study drug treatment
• Radiotherapy to multiple sites or immunotherapy within 14 days of initiation of study drug treatment (localized radiotherapy to a single site at least 7 days before start is permissible)
• Major surgery within 14 days of initiation of study drug treatment
• Participants in whom the required program of oral (PO) and IV fluid hydration is contraindicated
• Prior history of a hypersensitivity reaction to PLD, doxorubicin, bortezomib, carfilzomib, or liposomal drug formulations other than PLD; history of reactions to liposomal drug formulations other than PLD should be evaluated individually and if their reactions were felt to have been due to the encapsulated agent, rather than the liposomal component itself they should be excluded at the discretion of the investigators
• Participants who are known to have active hepatitis A, B, or C viral infection may not participate in this study; active disease is defined as participants with a known viral hepatitis whose liver function tests are elevated
• Compromised cardiovascular function defined as any of the following:
• Electrocardiogram (EKG) evidence of acute ischemia
• EKG evidence of medically significant conduction system abnormalities
• History of myocardial infarction within the last 6 months

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Schroeder MA, Fiala MA, Huselton E, Cardone MH, Jaeger S, Jean SR, Shea K, Ghobadi A, Wildes T, Stockerl-Goldstein KE, Vij R. A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma. Clin Cancer Res. 2019 Jul 1;25(13):3776-3783. doi: 10.1158/1078-0432.CCR-18-1909. Epub 2019 Apr 5.

  PMID: 30952640 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; liposomal doxorubicin; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; 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

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

Results Point of Contact

• Title: Ravi Vij, M.D.
• Organization: Washington University School of Medicine

rvij@wustl.edu

314-454-8304

Study Officials

• Ravi Vij, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: November 15, 2010
• First Posted: November 23, 2010
• Study Start: May 14, 2012
• Primary Completion: December 28, 2017
• Study Completion: March 23, 2018
• Last Updated: April 8, 2019
• Results First Posted: April 8, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)