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Irinotecan

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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.

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.

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.

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.

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.

Carfilzomib

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.

Susanne M Arnold, MD

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.

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.

A total of 16 patients were enrolled to the Phase 1b run-in at 3 different dosing levels:

4 patients into Dosing Level 1: 20/27 mg/m\^2 Carfilzomib, 125 mg/m\^2 Irinotecan

9 patients into Dosing Level 2: 20/27 mg/m\^2 Carfilzomib, 125 mg/m\^2 Irinotecan

3 patients into Dosing Level 3: 20/27 mg/m\^2 Carfilzomib, 125 mg/m\^2 Irinotecan

A total of 62 patients were enrolled into the Phase 2 trial. The Phase 2 component is a single-arm component, with participants stratified into two groups:

37 platinum-sensitive

25 platinum-refractory

Enrollment was not sequential, as all participants in the Phase 2 component were different individuals than the participants enrolled into the Phase 1b component.

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

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

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.

Estimate of 6-month overall survival (OS) rate of relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan.

The survival function was estimated using the Kaplan-Meier method, with overall survival defined as time from enrollment until death. Patients with no date of death were censored at the time of last contact.

Rate of overall response of relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan.

Responses were evaluated by the criteria defined in RECIST v1.1. Patients were categorized at each response assessment as having one of the following:

complete response (CR) partial response (PR) stable disease (SD) progressive disease (PD) not assessable (NA)

Overall response rate is defined as the proportion of patients achieving a best response of PR or better while on study; in other words, the proportion of patients achieving a CR or PR while on study.

Estimate of 6-month progression-free survival (PFS) rate of relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan.

The survival function was estimated using the Kaplan-Meier method, with progression-free survival defined as time from enrollment until disease progression or death. Patients with no date of death and no date of disease progression were censored at the time of last contact.

Number of Dose Limiting Toxicity (DLT) adverse events related to Carfilzomib in combination with Irinotecan administration. Subjects were 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

Lucille P. Markey Cancer Center at University of Kentucky

Washington University School of Medicine

Cancer Research and Biostatistics Clinical Trials Consortium

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

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

Phase Ib Cohort 3: 20/45 mg/m^2 Carfilzomib, 125 mg/m^2 Irinotecan

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.

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

Director of Quality and Regulatory Compliance

MTD for Cycle 1 Day 1 and Day 2 doses

MTD for all doses after Cycle 1 Days 1 and 2

16 total subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers. Subjects were given Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in a standard 3+3 dose-finding design.

Phase 1b: All Patients Enrolled for MTD Determination of Carfilzomib With Irinotecan

Subjects with relapsed small and non-small cell lung cancer or other irinotecan-sensitive cancers. Subjects were given Carfilzomib (Day 1,2,8,9, 15, and 16) in combination with Irinotecan (Days 1, 8, 15) in a standard 3+3 dose-finding design.

Phase Ib: Maximum Tolerated Dose

Initial response to platinum-based chemotherapy with progression \> 90 days after last treatment.

Platinum Sensitive 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.

Platinum Refractory Disease

A total of 62 eligible relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan.

Phase II: Overall Survival Rate at 6 Months

Phase II: Platinum Sensitive Disease

No response to platinum-based chemotherapy or progression within 90 days of completing platinum-based therapy. Subjects who progressed within 1 month of completed platinum-based chemotherapy were excluded.

Phase II: Platinum Refractory Disease

Relapsed small cell lung cancer patients treated with Carfilzomib in combination with Irinotecan.

Overall Response Rate

Phase II: Progression-Free Survival Rate at 6 Months

Dehydration

Diarrhea

Phase Ib: Dose Limiting Toxicities

Phase Ib Cohort 1: 20/27 mg/m^2 Carfilzomib, 125 mg/m2 Irinotecan

Phase Ib Cohort 2: 20/36 mg/m^2 Carfilzomib, 125 mg/m2 Irinotecan

Phase Ib Cohort 3: 20/45 mg/m^2 Carfilzomib, 125 mg/m2 Irinotecan

Phase II: Stratified, single arm trial, starting dose of 20/36 mg/m2 of carfilzomib and 125 mg/m2 of irinotecan, small cell lung cancer patients who relapsed on a prior platinum regimen.

Stratification:

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 who progressed within 1 month of completed platinum-based chemotherapy were excluded.

Carfilzomib: 20/36 mg/m2 stepped up dosing, IV infusion (30 min), days 1, 2, 8, 9, 15 and 16 of each 28 day cycle. # cycles: 6, until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Irinotecan: 125 mg/m2, IV infusion (90 min), days 1, 8, 15 of each 28 day cycle. # cycles: 6, until progression, or unacceptable toxicity, or treatment delay for any reason greater than 3 weeks.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies and Small Cell Lung Cancer Patients	NCT01941316	Small Cell Lung... Non Small Cell ... Irinotecan Sens...	Carfilzomib Irinotecan	18 Years -	Cancer Research and Biostatistics Clinical Trials Consortium
Study of Carfilzomib With Irinotecan in Irinotecan-Sensitive Malignancies and Small Cell Lung Cancer Patients	NCT01941316	Small Cell Lung... Non Small Cell ... Irinotecan Sens...	Carfilzomib Irinotecan	18 Years -	Cancer Research and Biostatistics Clinical Trials Consortium

Spots Global Cancer Trial Database for irinotecan sensitive cancers