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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Small Cell Lung Carcinoma, Non Small Cell Lung Carcinoma, Irinotecan Sensitive Cancers

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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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 SGOT and SGPT ≤ 2 x the institutional upper limit of normal all obtained within 14 days prior to enrollment. Patients must have an 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: Phase Ib: 0 or 1 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, 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II<br>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: Platinum sensitive disease: initial response to platinum-based chemotherapy with progression > 90 days after last treatment. 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. | Drug: Carfilzomib<br>* 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.<br>* Other names: Kyprolis;Drug: Irinotecan<br>* 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.<br>* Other names: Campto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 28 Days | 
| Phase II: Assess 6 month survival of relapsed small cell lung cancer patients treated with Carfilzomib in combination with irinotecan. | Assess 6 month survival of relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan . | up to 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate |  | up to 6 months | 
| Progression-free survival |  | up to 6 months | 
| Safety/tolerability and the rates of specific adverse events | 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. Non-hematologic: ≥ 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 Hematologic: 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 | up to 6 months | 
| Biomarker endpoint | Carfilzomib proteasome chymotrypsin-like activity in PBMC and LMP7 and b5 expression. | Day 1: pre-dose, 90min, 2hr., 5.5hr post dose; Day 2: pre-dose | 
| Biomarker endpoint | Irinotecan-mediated DNA damage by immunofluorescence analysis for gamma-H2AX staining. | Day 1: pre-dose, 90min, 2hr., 5.5hr post dose; Day 2: pre-dose | 
| Biomarker endpoint | Western blot analysis for Topoisomerase-I expression. | Day 1: pre-dose, 90min, 2hr., 5.5hr post dose; Day 2: pre-dose | 
| Biomarker endpoint | When available, banked tumor tissue for immunohistochemical expression of Topoisomerase-I. | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carfilzomib, Irinotecan, Small Cell Lung Cancer, Non Small Cell Lung Cancer, Ovarian Cancer, Gastric Cancer, Esophageal Cancer, Cervical Cancer