Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Lung Cancer, Non-Small-Cell Lung Cancer, NSCLC
Brief summary
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.
Interventions
DRUGXL184
Capsules administered orally daily
DRUGerlotinib
Tablets administered orally daily.
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | From initial dose up to 160 weeks | Treatment duration was defined as the number of days from the first dose to the last dose (measured in weeks), including any days of treatment interruption that occurred before the last dose of study drug. |
| Phase 2: Objective Response Rate (ORR) | From initial dose up to 72 weeks | Objective Response Rate is defined as the number of participants for whom the best overall response is complete (CR) or partial response (PR) confirmed by repeat assessments no less than four weeks after the criteria for the initial response were first met. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Duration of Response (DOR) in Participants With a CR or PR | From initial dose up to 72 weeks | DOR was defined as the time interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. |
| Phase 2: Progression-Free Survival (PFS) | From initial dose up to 72 weeks | Progression-free survival is defined as the time from first dose of cabozantinib to disease progression per protocol-defined criteria or death due to any cause, whichever occurs first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1-Cohort 1 75 mg PO qd cabozantinib, 150 mg PO qd erlotinib | 3 |
| Phase 1-Cohort 2A 75 mg PO qd cabozantinib, 100 mg PO qd erlotinib | 15 |
| Phase 1-Cohort 2B 50 mg PO qd cabozantinib, 150 mg PO qd erlotinib | 17 |
| Phase 1-Cohort 3A 125 mg PO qd cabozantinib, 100 mg PO qd erlotinib | 15 |
| Phase 1-Cohort 4A 125 mg PO qd cabozantinib, 50 mg PO qd erlotinib | 14 |
| Phase 2-cabozantinib cabozantinib single agent 125 mg | 15 |
| Phase 2-cabozantinib + Erlotinib 125 mg cabozantinib qd and 50 mg erlotinib | 13 |
| Total | 92 |
Baseline characteristics
| Characteristic | Phase 2-cabozantinib | Total | Phase 1-Cohort 1 | Phase 1-Cohort 2A | Phase 1-Cohort 2B | Phase 1-Cohort 3A | Phase 1-Cohort 4A | Phase 2-cabozantinib + Erlotinib |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 32 Participants | 1 Participants | 7 Participants | 5 Participants | 3 Participants | 7 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 60 Participants | 2 Participants | 8 Participants | 12 Participants | 12 Participants | 7 Participants | 7 Participants |
| Age, Continuous | 54.7 years | 59.8 years | 56.1 years | 61.6 years | 61.4 years | 57 years | 64.5 years | 64.8 years |
| Sex: Female, Male Female | 12 Participants | 63 Participants | 3 Participants | 9 Participants | 13 Participants | 10 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 29 Participants | 0 Participants | 6 Participants | 4 Participants | 5 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 15 / 15 | 17 / 17 | 15 / 15 | 14 / 14 | 15 / 15 | 12 / 13 |
| serious Total, serious adverse events | 1 / 3 | 7 / 15 | 8 / 17 | 8 / 15 | 7 / 14 | 5 / 15 | 11 / 13 |
Outcome results
Primary
Phase 1: Duration of Exposure of Cabozantinib With Erlotinib
Treatment duration was defined as the number of days from the first dose to the last dose (measured in weeks), including any days of treatment interruption that occurred before the last dose of study drug.
Time frame: From initial dose up to 160 weeks
Population: Safety Population was defined as all participants who received at least one dose of cabozantinib.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1 - Cohort 1 | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Cabozantinib (XL184) | 4.43 Weeks |
| Phase 1 - Cohort 1 | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Erlotinib | 6.57 Weeks |
| Phase 1 - Cohort 2A | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Cabozantinib (XL184) | 8.14 Weeks |
| Phase 1 - Cohort 2A | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Erlotinib | 10.29 Weeks |
| Phase 1 - Cohort 2B | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Cabozantinib (XL184) | 8.00 Weeks |
| Phase 1 - Cohort 2B | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Erlotinib | 10.00 Weeks |
| Phase 1 - Cohort 3A | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Erlotinib | 22.00 Weeks |
| Phase 1 - Cohort 3A | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Cabozantinib (XL184) | 17.00 Weeks |
| Phase 1 - Cohort 4A | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Cabozantinib (XL184) | 20.07 Weeks |
| Phase 1 - Cohort 4A | Phase 1: Duration of Exposure of Cabozantinib With Erlotinib | Erlotinib | 22.07 Weeks |
Primary
Phase 2: Objective Response Rate (ORR)
Objective Response Rate is defined as the number of participants for whom the best overall response is complete (CR) or partial response (PR) confirmed by repeat assessments no less than four weeks after the criteria for the initial response were first met.
Time frame: From initial dose up to 72 weeks
Population: ORR was assessed using the efficacy measurable population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 - Cohort 1 | Phase 2: Objective Response Rate (ORR) | 1 Participants |
| Phase 1 - Cohort 2A | Phase 2: Objective Response Rate (ORR) | 0 Participants |
Secondary
Phase 2: Duration of Response (DOR) in Participants With a CR or PR
DOR was defined as the time interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause.
Time frame: From initial dose up to 72 weeks
Population: Safety Population was defined as all participants who received at least one dose of cabozantinib. 'Overall number of participants analyzed' = participants evaluable for this Outcome Measure.~There were zero responders in Phase 2 - ARM 2, Cabozantinib + Erlotinib arm. So, no data was derived for this endpoint for this arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Phase 2: Duration of Response (DOR) in Participants With a CR or PR | NA Weeks |
Secondary
Phase 2: Progression-Free Survival (PFS)
Progression-free survival is defined as the time from first dose of cabozantinib to disease progression per protocol-defined criteria or death due to any cause, whichever occurs first.
Time frame: From initial dose up to 72 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Phase 2: Progression-Free Survival (PFS) | 1.91 months |
| Phase 1 - Cohort 2A | Phase 2: Progression-Free Survival (PFS) | 3.94 months |