A Study of XL184 (Cabozantinib) With or Without Erlotinib in Subjects With Non-Small Cell Lung Cancer (NSCLC)

A Phase 1b/2 Study of XL184 With or Without Erlotinib in Subjects With Non-Small Cell Lung Cancer

The study consisted of a Phase 1 dose escalation/dose de-escalation portion to determine a safe and tolerable combination dose(s) of cabozantinib and erlotinib, and a Phase 2 Simon optimal 2-stage design portion with randomized assignment of subjects in an equal ratio to determine the objective response rate (ORR) of cabozantinib with or without erlotinib in subjects with non-small cell lung cancer (NSCLC) who have progressed after responding to treatment with erlotinib. The doses of cabozantinib used in this study were based on the salt weight, not the freebase weight.

Inclusion Criteria-Phase 1:

• Subjects had pathologically confirmed NSCLC and currently have Stage IIIb or IV NSCLC
• Subjects had failed treatment with erlotinib at 150 mg qd
• Subjects had tolerated erlotinib at the dose of the cohort in which they were enrolled (or at a higher dose) for at least 6 weeks (or for the duration of treatment if disease progression had occurred during treatment with erlotinib for less than 6 weeks)
• The subject was at least 18 years old
• The subject had an ECOG performance status of < 2
• The subject had organ and marrow function as follows: - absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9 g/dL, bilirubin ≤ 1.5 times the upper limit of normal, serum creatinine ≤ 1.5 mg/dL or if serum creatinine > 1.5 mg/dL calculated creatinine clearance ≥ 60 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal, amylase and lipase < 1.5 times the upper limit of normal
• Sexually active subjects had to agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments (excluding women who are not of child bearing potential and men who have been sterilized)
• Female subjects of childbearing potential had to have a negative pregnancy test at enrollment. Females of childbearing potential were defined as sexually mature women without prior hysterectomy or who had evidence of menses in the past 12 months. However, women who had been amenorrheic for 12 or more months were still considered to be of childbearing potential if the amenorrhea was possibly due to prior chemotherapy, antiestrogens, or ovarian suppression
• The subject had no other diagnosis of malignancy (unless non-melanoma skin cancer, carcinoma in situ of the cervix, or a malignancy diagnosed ≥ 2 years previously, and currently with no evidence of disease)

Exclusion Criteria-Phase 1:

• The subject had received anti-cancer treatment (eg, chemotherapy, radiotherapy, cytokines, or hormones) within 4 weeks with exception of erlotinib (6 weeks for nitrosoureas or mitomycin C) before the first dose of study drug
• The subject had not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade ≤1 from clinically significant adverse events (AEs) due to antineoplastic agents, investigational drugs, or other medications that were administered prior to study enrollment
• The subject had symptomatic or uncontrolled brain metastases requiring current treatment, including steroids and anticonvulsants
• The subject had a history of clinically significant hematemesis or a recent history of hemoptysis of > 0.5 teaspoon of red blood or other signs indicative of pulmonary hemorrhage
• The subject had the presence of cavitation, endobronchial lesion or a lesion abutting a major blood vessel
• The subject had serious intercurrent illness, such as uncontrolled hypertension (sustained blood pressure [BP] readings of > 140 mmHg systolic or > 90 mmHg diastolic not controlled with anti-hypertensive medication), unhealed wounds from recent surgery or clinically significant cardiac arrhythmias or a recent history of significant disease such as either symptomatic congestive heart failure or unstable angina pectoris within 3 months or myocardial infarction within 6 months before the first dose of study drug
• The subject was pregnant or breastfeeding
• The subject had an active infection requiring systemic treatment
• The subject had an allergy or hypersensitivity to components of either the cabozantinib or erlotinib formulations
• The subject was incapable of understanding and complying with the protocol or unable to provide informed consent

Inclusion Criteria-Phase 2

• Subjects had pathologically confirmed NSCLC and currently have Stage IIIb or IV NSCLC
• Subjects had: Documented radiological PD, following a prior response, per investigator assessment, to monotherapy with erlotinib, OR; Documented radiological PD, per investigator assessment, following stable disease of at least 6 months on monotherapy with erlotinib
• Subjects who had received subsequent anti-cancer therapy after having progressed on erlotinib (as defined above) also had to have documented radiological PD per investigator assessment to their most recent anti-cancer therapy. If the most recent anti-cancer therapy was erlotinib after having previously progressed on erlotinib (as defined above) the subject also had to have documented radiological PD per investigator assessment to their most recent course of erlotinib
• Subjects had to have tolerated erlotinib at the maximal dose that would be administered in Phase 2 (or at a higher dose) for a minimum of 6 weeks
• Subjects had measurable disease per RECIST
• Subjects had to have 15 unstained consecutive slides of archival or fresh tumor tissue (from one tumor block, frozen tumor tissue, or a paraffin block) identified and designated for shipment to the sponsor if permitted by local regulations (including IRB [Institutional Review Board] policies). The eligibility of subjects with < 15 unstained slides of available archival tissue was discussed with the sponsor
• The subject was at least 18 years old
• The subject had an ECOG performance status of < 1
• The subject had organ and marrow function as follows: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9 g/dL, bilirubin ≤ 1.5 times the upper limit of normal, serum creatinine ≤ 1.5 mg/dL or if serum creatinine > 1.5 mg/dL calculated creatinine clearance ≥ 60 mL/min, ALT and AST ≤ 2.5 times the upper limit of normal, amylase and lipase < 1.5 times the upper limit of normal
• Sexually active subjects had to agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments (excluding women who are not of child bearing potential and men who have been sterilized)
• Female subjects of childbearing potential had to have a negative pregnancy test at enrollment. Females of childbearing potential were defined as sexually mature women without prior hysterectomy or who had evidence of menses in the past 12 months. However, women who had been amenorrheic for 12 or more months were still considered to be of childbearing potential if the amenorrhea was possibly due to prior chemotherapy, antiestrogens, or ovarian suppression
• The subject had no other diagnosis of malignancy (unless non-melanoma skin cancer, carcinoma in situ of the cervix, or a malignancy diagnosed ≥ 2 years previously, and currently with no evidence of disease)

Exclusion Criteria-Phase 2

• The subject had received: Small molecule inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2)/ kinase insert domain receptor (KDR) at anytime, OR; An investigational anti-cancer agent within 4 weeks of the first dose of study drug, OR; Investigational small molecule inhibitors of EGFR at any time, OR; A small molecule inhibitor of epidermal growth factor (EGF)/EGFR at any time (with the exception of erlotinib and gefitinib), OR; Anti-cancer therapy, including radiation therapy, within 4 weeks of the first dose of study drug (with the exception of gefitinib and erlotinib), OR; Prior therapy with a c-Met inhibitor. Recent (within 3 months) radiation therapy to the thoracic cavity including brachytherapy, unless radiation therapy targeted only bone metastasis
• The subject had not recovered to NCI CTCAE v3.0 Grade ≤1 from clinically significant AEs due to antineoplastic agents, investigational drugs, or other medications that were administered prior to study enrollment
• The subject had symptomatic or uncontrolled brain metastases requiring current treatment, including steroids and anticonvulsants
• The subject had experienced clinically significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood within 3 months before the first dose of study treatment, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The subject had cavitating pulmonary lesion(s), known endobronchial disease or a pulmonary lesion abutting or encasing a major blood vessel
• The subject had serious intercurrent illness, such as uncontrolled hypertension (sustained BP readings of > 140 mmHg systolic or > 90 mmHg diastolic not controlled with anti hypertensive medication), unhealed wounds from recent surgery or clinically significant cardiac arrhythmias or a recent history of significant disease such as either symptomatic congestive heart failure or unstable angina pectoris within the past 3 months, myocardial infarction, stroke, or transient ischemic attack within the past 6 months
• The subject was pregnant or breastfeeding
• The subject had a clinically significant active infection requiring systemic treatment
• The subject had an allergy or hypersensitivity to components of either the cabozantinib or erlotinib formulations
• The subject was incapable of understanding and complying with the protocol or unable to provide informed consent
• The subject had a history of idiopathic pulmonary fibrosis or interstitial lung disease (ILD)