Patient case: 71-year-old female with lung cancer; genetic feature: ROS1

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

Summary: The purpose of this study is to determine a well-tolerated dose of Carfilzomib in combination with Irinotecan 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.

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 extensive disease dissemination at presentation and the overall prognosis remains poor, with a 2-year overall survival of less than 5% and a median survival of approximately 9-11 months. 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.
  Proteasome inhibition affects the levels of numerous cell cycle control proteins, apoptosis, cell adhesion, angiogenesis, and chemoresistance proteins. Carfilzomib and other proteasome inhibitors interrupt cellular pathways integral to the survival of small cell lung cancer, namely the dysregulated apoptotic pathway involving activated nuclear factor-kB (NF-kB). NF-kB activates the transcription of anti-apoptotic and proliferation genes, mediating tumor cell survival in response to cytotoxic stress and resulting in chemoresistance, a common problem in small cell lung cancer. Carfilzomib prevents proteasomal degradation of IkB, the inhibitor of NF-kB, and also modulates 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, is an important problem in SCLC, the vast majority of SCLC cases have bcl-2 overexpression, and low levels of bcl-2 and b1-integrin are associated with improved survival in SCLC.
  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.
  Irinotecan, a camptothecins, inhibits topoisomerase I. As a class, camptothecins have shown efficacy in small cell lung cancer in a variety of settings. 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. Le Chevalier and colleagues used an every 3-week schedule of irinotecan, 350 mg/m2, given to 32 chemotherapy-naive SCLC subjects and showed an objective response rate of 16% and a median survival of 4.5 months. Thus, the median survival of camptothecins in the second -line setting in SCLC ranges from 24 to 35 weeks, with those subjects in sensitive relapse having a median survival of 4 to 8 weeks longer than those with refractory relapse. The use of Carfilzomib in combination with Irinotecan, a topoisomerase inhibitor, is expected to differ from previous efforts with other proteasome inhibitors because of its sustained proteasome inhibition and its potential synergy with this class of drugs.
  For Phase 1b patients will be entered onto dosing cohorts of 3 patients. At least three patients at each dose level must have completed cycle one before the study leadership (principal investigators and Study statisticians) will allow patients to be enrolled onto the successive dose level.
  Dose-limiting toxicities (DLTs) will be defined according to the National Cancer Institute's CTCAE v.4.0 toxicity scale.
  For Phase 2 patients will be treated with the Maximum Tolerated Dose (MTD) of Carfilzomib determined in Phase 1b and 125mg/m2 of Irinotecan.

Eligibility: Inclusion Criteria:
  -  Patients must have histologically or cytologically-confirmed diagnosis of progressive or recurrent malignancy as follows:
  -  Phase Ib: advanced small or non-small cell lung cancer, or other cancer in which irinotecan therapy has been shown to be effective and for whom no curative therapy exists. Patients who received primary curative chemoradiation therapy, 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 cancer do not require a confirmatory biopsy to be eligible for this trial. No limit will be placed on prior regimens received, but prior irinotecan is not allowed.
  -  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:
  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, 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.

Relevance to patient case: not relevant