Study of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies and Small Cell Lung Cancer Patients
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|ClinicalTrials.gov Identifier: NCT01941316|
Recruitment Status : Recruiting
First Posted : September 13, 2013
Last Update Posted : November 7, 2017
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/m2 with Irinotecan dosed at 125 mg/m2. 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.
|Condition or disease||Intervention/treatment||Phase|
|Small Cell Lung Carcinoma Non Small Cell Lung Carcinoma Irinotecan Sensitive Cancers||Drug: Carfilzomib Drug: Irinotecan||Phase 1 Phase 2|
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 a tetrapeptide epoxyketone, similar to epoxomicin.
Carfilzomib and other proteasome inhibitors interrupt cellular pathways integral to the survival of small cell lung cancer, namely the apoptic pathway involving activated nuclear factor-kB (or 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 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 SCLC 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 25/30 mg/m2 as stepped up dosing determined in Phase 1b and 125mg/m2 of Irinotecan.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||112 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 1b/II Trial of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies (Phase Ib) and Small Cell Lung Cancer Patients (Phase II) Who Have Progressed on Prior Platinum-based Chemotherapy|
|Study Start Date :||November 2013|
|Estimated Primary Completion Date :||December 2018|
|Estimated Study Completion Date :||December 2018|
Experimental: Phase II
Phase II: Stratified, single arm trial using a starting dose of 20/36 mg/m2 of carfilzomib and 125 mg/m2 of irinotecan, in small cell lung cancer patients who have relapsed on a prior platinum regimen.
Stratification for phase II component:
20/36 * mg/m2 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.
125 mg/m2, 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 1b: Determine maximum tolerated dose of Carfilzomib in combination with Irinotecan in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers. [ Time Frame: 28 Days ]Determine maximum tolerated dose (MTD) of Carfilzomib in combination with Irinotecan in subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers.
- Phase II: Assess 6 month survival of relapsed small cell lung cancer patients treated with Carfilzomib in combination with irinotecan. [ Time Frame: up to 6 Months ]Assess 6 month survival of relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan .
- Response rate [ Time Frame: up to 6 months ]
- Progression-free survival [ Time Frame: up to 6 months ]
- Safety/tolerability and the rates of specific adverse events [ Time Frame: up to 6 months ]
Number of patients with adverse events as a measure of safety and tolerability. Dose Limiting Toxicity (DLT) adverse events related to Carfilzomib in combination with Irinotecaen administration. Subjects will be evaluated for toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) of version 4.0.
A DLT is defined as any of the treatment emergent toxicities with attribution to one or more of the study drugs that occur during Cycle 1.
- ≥ Grade 2 neuropathy with pain
- ≥ Any Grade 3 or 4 toxicity (excluding nausea, vomiting, diarrhea or grade 3 fatigue)
- ≥ Grade 3 nausea, vomiting, or diarrhea lasting > 7 days despite maximal antiemetic/antidiarrheal therapy
- ≥ Grade 4 fatigue lasting for ≥ 7 days
Grade 4 neutropenia lasting for ≥ 7 days, Febrile neutropenia, Grade 4 thrombocytopenia lasting ≥ 7 days despite dose delay, Grade 3-4 thrombocytopenia associated with bleeding
- Biomarker endpoint [ Time Frame: Day 1: pre-dose, 90min, 2hr., 5.5hr post dose; Day 2: pre-dose ]Carfilzomib proteasome chymotrypsin-like activity in PBMC and LMP7 and b5 expression.
- Biomarker endpoint [ Time Frame: Day 1: pre-dose, 90min, 2hr., 5.5hr post dose; Day 2: pre-dose ]Irinotecan-mediated DNA damage by immunofluorescence analysis for gamma-H2AX staining.
- Biomarker endpoint [ Time Frame: Day 1: pre-dose, 90min, 2hr., 5.5hr post dose; Day 2: pre-dose ]Western blot analysis for Topoisomerase-I expression.
- Biomarker endpoint [ Time Frame: Day 1 ]When available, banked tumor tissue for immunohistochemical expression of Topoisomerase-I.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01941316
|Contact: Susanne M Arnold, MDfirstname.lastname@example.org|
|Contact: Grace Powell, BAemail@example.com|
|United States, Arizona|
|Cancer Treatment Centers of America, Western Regional Medical Center||Completed|
|Goodyear, Arizona, United States, 85338|
|United States, California|
|Cedars-Sinai Medical Center||Withdrawn|
|Los Angeles, California, United States, 90048|
|Santa Monica, California, United States, 90404|
|United States, Kentucky|
|University of Kentucky Markey Cancer Center||Recruiting|
|Lexington, Kentucky, United States, 40536|
|Contact: Susanne M Arnold, MD 859-323-8043 firstname.lastname@example.org|
|Principal Investigator: Susanne M Arnold, MD|
|Norton Cancer Institute||Recruiting|
|Louisville, Kentucky, United States, 40202|
|Contact: John Hamm, MD 502-629-1234 John.email@example.com|
|Principal Investigator: John Hamm, MD|
|United States, Missouri|
|Washington University School of Medicine||Recruiting|
|Saint Louis, Missouri, United States, 63110|
|Contact: Maria Baggstrom, MD MBaggstr@DOM.wustl.edu|
|Contact: Kristina Williams (314) 362-6963 firstname.lastname@example.org|
|Principal Investigator: Maria Baggstrom, MD|
|United States, Oregon|
|Providence Portland Medical Center | Earle A. Chiles Research Institute||Recruiting|
|Portland, Oregon, United States, 97213|
|Contact: Rachel E Sanborn, MD 503-215-5696 Rachel.Sanborn@providence.org|
|Principal Investigator: Rachel E Sanborn, MD|
|United States, Texas|
|University of Texas Medical Branch at Galveston||Recruiting|
|Galveston, Texas, United States, 77555|
|Contact: Steven P Rivas 409-772-0574 email@example.com|
|Contact: Nakia Watson 409-772-0575 firstname.lastname@example.org|
|Principal Investigator: Maurice Willis, MD|
|United States, Washington|
|Virginia Mason Cancer Institute||Recruiting|
|Seattle, Washington, United States, 98111|
|Contact: Emma Bishop 206-341-8979 email@example.com|
|Principal Investigator: Joseph Rosales, MD|
|United States, Wisconsin|
|Aurora Research Institute | Aurora Cancer Care||Recruiting|
|Wauwatosa, Wisconsin, United States, 53226|
|Contact: Michael Thompson, MD, PhD 414-219-7838 Michael.A.Thompson@aurora.org|
|Principal Investigator: Michael Thomson, MD, PhD|
|Principal Investigator:||Susanne M Arnold, MD||Lucille P. Markey Cancer Center at University of Kentucky|