Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma

NCT ID: NCT00531284

Last Updated: 2017-08-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 184 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-09-30
• Study Completion Date: 2017-05-22

Brief Summary

The primary objectives of this Phase 1b/2 study were as follows:

• Phase 1b (Bolus and Infusion): To evaluate the safety and tolerability of carfilzomib in patients with relapsed solid tumors and in patients with relapsed and/or refractory multiple myeloma and in patients with refractory lymphoma.
• Phase 2 (Bolus): To evaluate the overall response rate (ORR) after 4 cycles of carfilzomib in patients with relapsed solid tumors.

Conditions

Ovarian Cancer; Renal Cancer; Non-small Cell Lung Cancer; Small Cell Lung Cancer; Solid Tumors; Multiple Myeloma; Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 1B Solid Tumors: Carfilzomib 20 mg/m² Bolus

Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 20/27 mg/m² Bolus

Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 20/36 mg/m² Bolus

Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 2 Solid Tumors: Carfilzomib 20/36 mg/m² Bolus

Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 36 mg/m²

Participants received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 45 mg/m²

Participants received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 20/45 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 20/56 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1B Solid Tumors: Carfilzomib 20/70 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b Multiple Myeloma: Carfilzomib 20/36 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b Multiple Myeloma: Carfilzomib 20/45 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b Multiple Myeloma: Carfilzomib 20/56 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b Multiple Myeloma: Carfilzomib 20/70 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b Lymphoma: Carfilzomib 20/56 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b Lymphoma: Carfilzomib 20/70 mg/m²

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Phase 1b MM: Carfilzomib 20/45 mg/m² + Dexamethasone

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Dexamethasone

Intervention Type: DRUG

Administered orally or by IV infusion prior to carfilzomib

Phase 1b MM: Carfilzomib 20/56 mg/m² + Dexamethasone

Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Dexamethasone

Intervention Type: DRUG

Administered orally or by IV infusion prior to carfilzomib

Interventions

Carfilzomib

Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion

Intervention Type: DRUG

Dexamethasone

Administered orally or by IV infusion prior to carfilzomib

Intervention Type: DRUG

Other Intervention Names

Kyprolis

Eligibility Criteria

Inclusion Criteria

Disease related

Phase 1 Subjects (Bolus and Infusion):

Solid Tumor:

• Histologically confirmed advanced solid tumor
• 1 to 3 prior treatment regimens
• At least one site of radiographically measurable disease of ≥ 2 cm in the largest dimension by traditional computed tomography (CT) scanning technique or ≥ 1 cm in the largest dimension by spiral CT scanning (per Response Evaluation Criteria in Solid Tumors [RECIST] criteria); or if, in the Principal Investigator's opinion, evaluable disease can be reliably and consistently followed, the subject may be eligible upon approval by the Medical Monitor

Multiple Myeloma (MM):

• Relapsed and/or refractory multiple myeloma following 2 or more prior treatment regimens.
• Measurable disease as indicated by one or more of the following:
• Serum M-protein ≥ 1 g/dL
• Urine M-protein ≥ 200 mg/24 hr
• Serum Free Light Chain: Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is abnormal

Lymphoma:

• Histologically or cytologically confirmed lymphoma.
• Patients must have had an initial diagnosis of indolent non-Hodgkin lymphoma (NHL) (including follicular, small lymphocytic, lymphoplasmacytoid, and marginal zone lymphoma), indolent disease that transformed to a more aggressive subtype, as previously described or patients may have mantle cell lymphoma.
• Patients are required to have received prior rituximab (alone or combined with other treatment) and are considered refractory to (defined as no response, or progression within 6 months of completing therapy) or intolerant of continued rituximab.
• Patients may have received up to a maximum of four prior unique chemotherapy regimens, including if not contra-indicated autologous stem-cell transplantation (ASCT).
• For patients to enroll in the expanded dose group for lymphoma, patients must have measurable disease

Phase 2 Bolus Subjects:

-Histologically confirmed advanced solid tumor diagnosis and:

• Non-small cell lung cancer (NSCLC): Failed at least 1 prior platinum-based chemotherapy regimen but not more than 3 prior therapies for metastatic disease
• Small cell lung cancer (SCLC): Failed 1 to 3 prior chemotherapy regimens
• Ovarian: Failed at least 1 prior platinum-based chemotherapy regimen but not more than 4 therapies for metastatic disease
• Renal: Failed at least 2 prior chemotherapy regimens for metastatic disease
• Other solid tumor types: Failed at least 1 prior chemotherapy regimen for metastatic or relapsed disease and for which standard of care therapy is no longer effective or does not exist
• At least one site of radiographically measurable disease of ≥ 2 cm in the largest dimension by traditional CT scanning technique or ≥ 1 cm in the largest dimension by spiral CT scanning (per RECIST criteria); or if, in the Principal Investigator's opinion, evaluable disease can be reliably and consistently followed, the subject may be eligible upon approval by the Medical Monitor

Demographic

• Males and females ≥ 18 years of age
• Life expectancy of more than 3 months
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

Laboratory

• Adequate hepatic function, with bilirubin 1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) 3 times ULN
• Absolute neutrophil count (ANC) > 1000/mm³, hemoglobin ≥ 8 gm/dL for solid tumors or 7.0 gm/dL for MM, and platelet count ≥ 100,000/mm³ for solid tumors or ≥ 30,000/mm³ for MM.

• Subjects should not have received platelet transfusions for at least 1 week prior to screening
• Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for ≥ 2 weeks
• Subjects may receive red blood cell (RBC) transfusions or receive supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines
• Calculated or measured creatinine clearance (CrCl) of ≥ 20 mL/minute calculated using the formula of Cockcroft and Gault. Subjects with calculated CrCl < 20 mL/min may be allowed, only with prior approval by the Medical Monitor.

Ethical/Other

• Written informed consent in accordance with federal, local, and institutional guidelines
• Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose and agree to use dual methods of contraception during the study and for 3 months following the last dose of study drug. Post-menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements. Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.

Exclusion Criteria

Disease Related

• Chemotherapy with approved or investigational anticancer therapeutics, including steroid therapy, within 3 weeks prior to first dose or 6 weeks for antibody therapy
• Radiation therapy or immunotherapy within 3 weeks prior to first dose (except for antibody therapy, where 6 weeks is required); localized radiation therapy within 1 week prior to first dose
• Subjects with prior brain metastases are permitted, but must have completed treatment and have no evidence of active central nervous system (CNS) disease for at least 4 weeks prior to first dose
• For lymphoma patients; patients with prior stem cell transplant therapy (autologous SCT within the prior 8 weeks; allogeneic SCT within the prior 16 weeks). Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (GVHD)
• Evidence of CNS lymphoma
• Participation in an investigational therapeutic study within 3 weeks prior to first dose
• Prior treatment with carfilzomib

Concurrent Conditions

• Major surgery within 3 weeks prior to first dose
• Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 3 months prior to first dose
• Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose
• Known or suspected human immunodeficiency virus (HIV) infection or subjects who are HIV seropositive
• Active hepatitis A, B, or C infection
• Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose
• Subjects with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis
• Subjects at risk* in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment

• High risk for Tumor Lysis Syndrome.

Ethical / Other

• Female subjects who are pregnant or lactating
• Any clinically significant psychiatric or medical condition that in the opinion of the Investigator could interfere with protocol adherence or a subject's ability to give informed consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Pinnacle Oncology

Scottsdale, Arizona, United States

Tower Cancer Research Foundation

Beverly Hills, California, United States

Northwestern University

Chicago, Illinois, United States

University of Maryland Greenebaum Cancer Center

Baltimore, Maryland, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

The Sarah Cannon Research Institute

Nashville, Tennessee, United States

South Texas Accelerated Research Therapeutics (START)

San Antonio, Texas, United States

Countries

United States

References

Papadopoulos KP, Siegel DS, Vesole DH, Lee P, Rosen ST, Zojwalla N, Holahan JR, Lee S, Wang Z, Badros A. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015 Mar 1;33(7):732-9. doi: 10.1200/JCO.2013.52.3522. Epub 2014 Sep 15.

Reference Type: DERIVED

PMID: 25225420 (View on PubMed)

Ohshima-Hosoyama S, Davare MA, Hosoyama T, Nelon LD, Keller C. Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma. J Neurooncol. 2011 Dec;105(3):475-83. doi: 10.1007/s11060-011-0619-0. Epub 2011 Jun 3.

Reference Type: DERIVED

PMID: 21633906 (View on PubMed)

Other Identifiers

PX-171-007

Identifier Type: -

Identifier Source: org_study_id