Study of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies and Small Cell Lung Cancer Patients

NCT ID: NCT01941316

Last Updated: 2024-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2019-07-01

Brief Summary

The purpose of this study is to determine a well-tolerated dose of Carfilzomib in combination with Irinotecan (Phase 1b portion of the study) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers and to assess the 6 month survival of relapsed small cell lung cancer patients treated with this combination therapy. **The Phase 1b portion of the study is now complete**.

Phase 2 portion of the study. The safest, maximally tolerated dose established as established in Phase 1 for Phase 2 is as follows -- Carfilzomib will be provided at 20/36 mg/m^2 with Irinotecan dosed at 125 mg/m^2. The purpose of the Phase 2 portion of the study is to assess 6 month survival of relapsed small cell lung cancer ins subjects treated with this combination therapy.

Detailed Description

Small cell lung cancer accounts for approximately 15% of all lung cancer diagnoses in the United States (US), with 60-80% response rates to platinum-based chemotherapy in extensive disease. Despite its sensitivity to chemotherapy, small cell lung cancer is characterized by its tendency to spread to other locations in the body such as the bloodstream and other organs such as the liver. Currently, the only FDA-approved second-line therapies are oral and parenteral topotecan, although irinotecan is also commonly used in primary and relapsed disease. Novel combination therapies are desperately needed in this disease. in order to improve survival.

Carfilzomib (also known as Kyprolis) is an anti-cancer drug classified as a selective proteasome inhibitor. Proteasome inhibition affects the levels of numerous cell cycle control proteins, apoptosis (i.e., cell death), cell adhesion, angiogenesis, and chemoresistance proteins. Chemically, it is similar to epoxomicin.

Carfilzomib and other proteasome inhibitors interrupt cellular pathways integral to the survival of small cell lung cancer, namely the apoptotic pathway involving activated Nuclear Factor-kB (referenced as NF-kB). NF-kB activates the transcription of anti-apoptotic and proliferation genes, mediating tumor cell survival in response to cytotoxic stress thus resulting in chemoresistance, a common problem in small cell lung cancer. Carfilzomib prevents the breakdown of IkappaB (referenced as IkB), a protein which inhibits NF-kB, controls levels of the anti-apoptotic gene Bcl-2 and the tumor suppressor p53. Overexpression of Bcl-2, a key mediator of resistance to apoptosis following chemotherapy, which is an important problem in small cell lung cancer.

In this trial, Carfilzomib is combined with Irinotecan. Irinotecan, a camptothecins, inhibits topoisomerase I, thought to be important in the growth and spread of cancer. As a class, camptothecins have shown efficacy in small cell lung cancer in a variety of settings.

Topoisomerase-1 is thought to cause apoptosis via mechanisms other than NF-kB, adding to the potential synergy of these compounds. In addition, topoisomerase-1 is overexpressed in the majority of subjects with small cell lung cancer and decreased degradation of this enzyme is expected to lead to further enhancement of this mechanism of apoptosis

The pivotal phase III study which led to FDA approval of topotecan in relapsed small cell lung cancer was by Von Pawel et al, and included 211 subjects with sensitive (> 60 days since prior therapy) relapse and randomized them to either topotecan (107 subjects) daily for 5 days or to cyclophosphamide, doxorubicin, and vincristine (CAV), each given every 21 days. Topotecan showed no significant improvement in the median time to progression (13.3 weeks vs.12.3 weeks, p=0.552) or median survival (25 weeks vs. 24.7 weeks, p=0.795), however, subjects treated with topotecan had improvement in cancer-related symptoms (dyspnea, hoarseness, anorexia, and fatigue) as well as hematologic toxicity. Irinotecan, has established activity in small cell lung cancer, as well as non-small cell lung cancer, colorectal cancer and ovarian cancer.

In this Phase 2 study patients will be treated with the Maximum Tolerated Dose (MTD) of Carfilzomib 20/36 mg/m^2 as stepped up dosing determined in Phase 1b and 125mg/m^2 of Irinotecan.

Conditions

Small Cell Lung Carcinoma; Non Small Cell Lung Carcinoma; Irinotecan Sensitive Cancers

Study Design

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

Study Groups

Phase II

Phase II: Stratified, single arm trial using a starting dose of 20/36 mg/m^2 of carfilzomib and 125 mg/m^2 of irinotecan, in small cell lung cancer patients who have relapsed on a prior platinum regimen.

Stratification for phase II component:

1. Platinum sensitive disease: initial response to platinum-based chemotherapy with progression > 90 days after last treatment.

2. Platinum refractory disease: No response to platinum-based chemotherapy or progression within 90 days of completing platinum-based therapy. Subjects that progressed during or within one month of completion of platinum-based chemotherapy will be excluded.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

20/36 \* mg/m\^2 stepped up dosing, IV infusion (over 30 min), on days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Irinotecan

Intervention Type: DRUG

125 mg/m\^2, IV infusion (over 90 min), on days 1, 8, 15 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Phase Ib Cohort 1: 20/27 mg/m^2 Carfilzomib, 125 mg/m^2 Irinotecan

Cohort 1 of Phase Ib run-in to determine maximum tolerated dose (MTD) of Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.

Cohort 1 used a starting dose of 20/27 mg/m^2 of carfilzomib in combination with 125 mg/m^2 of irinotecan.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

20/36 \* mg/m\^2 stepped up dosing, IV infusion (over 30 min), on days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Irinotecan

Intervention Type: DRUG

125 mg/m\^2, IV infusion (over 90 min), on days 1, 8, 15 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Phase Ib Cohort 2: 20/36 mg/m^2 Carfilzomib, 125 mg/m^2 Irinotecan

Cohort 2 of Phase Ib run-in to determine maximum tolerated dose (MTD) of Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.

Cohort 2 used a starting dose of 20/36 mg/m^2 of carfilzomib in combination with 125 mg/m^2 of irinotecan.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

20/36 \* mg/m\^2 stepped up dosing, IV infusion (over 30 min), on days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Irinotecan

Intervention Type: DRUG

125 mg/m\^2, IV infusion (over 90 min), on days 1, 8, 15 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Phase Ib Cohort 1: 20/45 mg/m^2 Carfilzomib, 125 mg/m^2 Irinotecan

Cohort 3 of Phase Ib run-in to determine maximum tolerated dose (MTD) of Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.

Cohort 3 used a starting dose of 20/45 mg/m^2 of carfilzomib in combination with 125 mg/m^2 of irinotecan.

Group Type: EXPERIMENTAL

Carfilzomib

Intervention Type: DRUG

20/36 \* mg/m\^2 stepped up dosing, IV infusion (over 30 min), on days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Irinotecan

Intervention Type: DRUG

125 mg/m\^2, IV infusion (over 90 min), on days 1, 8, 15 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Interventions

Carfilzomib

20/36 \* mg/m\^2 stepped up dosing, IV infusion (over 30 min), on days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Intervention Type: DRUG

Irinotecan

125 mg/m\^2, IV infusion (over 90 min), on days 1, 8, 15 of each 28 day cycle. Number of cycles: 6, or until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Intervention Type: DRUG

Other Intervention Names

Kyprolis; Camptosar; Campto

Eligibility Criteria

Inclusion Criteria

• Patients must have histologically or cytologically-confirmed diagnosis of progressive or recurrent malignancy as follows:
• Phase II: extensive stage small cell lung cancer with progression or recurrence after exactly one platinum-containing regimen. Patients who progressed during or within one month of completing platinum-based chemotherapy will be excluded. Patients who received primary curative chemoradiation therapy for limited disease, but who recur within the primary tumor site, previously radiated field or with distant metastases are also allowed to participate. Patients who have clinical evidence of recurrent small cell lung cancer do not require a confirmatory biopsy to be eligible for this trial. Prior irinotecan is not allowed.
• Patients must have measurable disease per RECIST criteria 1.1 performed within 28 days prior to enrollment. All other required tests to assess non-measurable disease must be performed within 42 days prior to enrollment.
• Patients with known brain metastases are eligible only if he/she has been treated for brain metastasis, are asymptomatic after treatment, have a stable CT or MRI of the brain within 28 days of enrollment and are not receiving corticosteroid therapy to control symptoms from brain metastasis. Only a non-enzyme inducing anticonvulsant (e.g., Keppra) will be permitted for those patients requiring anticonvulsants. (Topical and/or inhaled steroids are allowed.)
• Patients may have received previous radiation therapy, but it must have been completed at least 21 days prior to enrollment and the patient should have recovered from all associated toxicities. Measurable or non-measurable disease must be present outside the previous radiation field or a new lesion inside the radiation port must be present.
• Patients may have received prior surgery provided that at least 28 days have elapsed since major surgery (thoracic or other major surgeries) and the patient has recovered from all associated toxicities. Patients must have disease outside of the previous surgical resection area or a new lesion must be present.
• Patients must have a serum creatinine ≤ the institutional upper limit of normal OR a creatinine clearance ≥ 60 cc/min, measured or calculated (Cockcroft-Gault formula), obtained within 14 days prior to registration.
• Patients must have adequate hepatic function as documented by a bilirubin ≤ 2 x the institutional upper limit of normal, an alkaline phosphatase ≤ 2 x the institutional upper limit of normal, and an Serum Glutamate Oxaloacetic Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) ≤ 2 x the institutional upper limit of normal all obtained within 14 days prior to enrollment.
• Patients must have an Absolute Neutrophil Count (ANC) ≥ 1,500/μl and a platelet count ≥ 100,000/μl obtained within 14 days prior to registration.
• Patients must be 18 years of age or older.
• Patients must have a Zubrod Performance Status as follows:

1. Phase Ib: 0 or 1

2. Phase II: 0, 1 or 2

• Patients must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
• Male subjects must agree to practice contraception.
• All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria

• No prior irinotecan or carfilzomib
• Must not have leptomeningeal metastases.
• Must be no anticipated need for concurrent radiation therapy during protocol treatment.
• Subjects that progressed during or within one month of completion of first-line platinum-based chemotherapy will be excluded.
• Patients must not be pregnant or lactating females.
• Must have had no major surgery within 28 days prior to enrollment.
• Must not have acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to enrollment.
• Must not have any known human immunodeficiency virus infection.
• Must not have known active or clinically significant hepatitis A, B or C infection.
• Must not have had any unstable angina or myocardial infarction within 4 months prior to enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.
• Must not have any uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment.
• Must not have any evidence of other clinically active cancer and have no history of prior malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal glands or pancreas.
• Must not have any significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to enrollment.
• Must not have any known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
• Must have no 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.
• Must not have 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.

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

Sponsors

Lucille P. Markey Cancer Center at University of Kentucky

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Cancer Research and Biostatistics Clinical Trials Consortium

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susanne M Arnold, MD

Role: PRINCIPAL_INVESTIGATOR

Lucille P. Markey Cancer Center at University of Kentucky

Locations

Cancer Treatment Centers of America, Western Regional Medical Center

Goodyear, Arizona, United States

University of Kentucky Markey Cancer Center

Lexington, Kentucky, United States

Norton Cancer Institute

Louisville, Kentucky, United States

Washington University School of Medicine

St Louis, Missouri, United States

Providence Portland Medical Center | Earle A. Chiles Research Institute

Portland, Oregon, United States

University of Texas Medical Branch at Galveston

Galveston, Texas, United States

Virginia Mason Cancer Institute

Seattle, Washington, United States

Aurora Research Institute | Aurora Cancer Care

Wauwatosa, Wisconsin, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CAR-IST-553

Identifier Type: OTHER

Identifier Source: secondary_id

CRAB CTC 11-001

Identifier Type: -

Identifier Source: org_study_id