Phase II Study of Pembrolizumab in Combination With Lenvatinib in Patients With TNBC, NSCLC, and Other Tumor Types and Brain Metastases
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Brain Metastases
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 104
- Locations
- 1
- Primary Endpoint
- To establish the intracranial ORR of the pembrolizumab and lenvatinib combination in patients with TNBC or NSCLC and brain metastases, as assessed according to the modified RECIST
- Status
- Recruiting
- Last Updated
- 16 days ago
Overview
Brief Summary
This is a single-center, open-label, multi-cohort Phase II study evaluating the efficacy and safety of pembrolizumab in combination with lenvatinib in patients with solid tumors and brain metastases.
The study will be comprised of 3 patient cohorts: triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and solid tumor types other than TNBC and NSCLC. Cohort 3 will be comprised of solid tumor types with established (e.g., renal cell carcinoma [RCC], endometrial cancer) or preliminary clinical evidence (e.g., gastric cancer, colorectal cancer) of efficacy of programmed cell death-1 (PD-1) and angiogenesis inhibitors. The study will be conducted using a Simon's optimal two-stage design, and approximately 87 patients will be enrolled concurrently (n=29 per cohort).
The primary endpoint is intracranial objective response rate (ORR) as assessed by the modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Detailed Description
Primary Objective: Objective: To determine the intracranial ORR of the pembrolizumab and lenvatinib combination in patients with TNBC or NSCLC and brain metastases, as assessed according to the modified RECIST (mRECIST) \[Qianet al., 2017\] (Appendix 1). Secondary Objectives: * Objective: To evaluate the safety and tolerability of the pembrolizumab and lenvatinib combination in patients with TNBC, NSCLC, and other solid tumor types and brain metastases, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. (Appendix 2). * To determine the intracranial ORR of the pembrolizumab and lenvatinib combination in patients with TNBC or NSCLC and brain metastases, as assessed according to the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) criteria (Appendix 3). * Objective: To determine intracranial progression-free survival (PFS) of the pembrolizumab and lenvatinib combination in patients with TNBC, NSCLC, and other solid tumor types --Objective: To determine the systemic ORR of the pembrolizumab and lenvatinib combination in patients with TNBC, NSCLC, and other solid tumor types and brain metastases, as assessed by the RECIST v1.1 (Appendix 4). * Objective: To evaluate systemic PFS in patients with TNBC, NSCLC, and other solid tumor types and brain metastases receiving the pembrolizumab and lenvatinib combination, as assessed by the RECIST v1.1. * Objective: To evaluate overall survival (OS) in patients with TNBC, NSCLC, and other solid tumor types and brain metastases receiving the pembrolizumab and lenvatinib combination. Exploratory Objectives * Objective: To identify the site of first progression. * Objective: To determine changes in dose, duration, and frequency of steroid use for symptomatic management of brain metastases. Patients who require at least 4 mg of dexamethasone/day for symptom management will be considered as requiring high-dose steroids. * Objective: To assess neurological function according to the Neurologic Assessment in Neuro-Oncology (NANO) scale (Appendix 5). * Objective: To evaluate immune-related biomarkers of response to the pembrolizumab and lenvatinib combination. * Objective: To identify imaging characteristics associated with pembrolizumab and lenvatinib treatment-induced immunological changes. * Objective: To evaluate the effects of the pembrolizumab and lenvatinib combination on cranial radiation and opiate pain medication use and seizure reduction. * Objective: Intracranial and systemic duration of response (DOR) in patients who achieve partial response (PR) or complete response (CR).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients are eligible to be included in the study only if all the following criteria apply:
- •Male/female patients who are at least 18 years of age on the day of signing informed consent with histologically or cytologically confirmed TNBC (Cohort 1), NSCLC (Cohort 2), or solid tumors other than TNBC and NSCLC (Cohort 3) with brain metastasis and with or without active extracranial disease will be enrolled in this study.
- •Has at least 1 measurable brain metastasis: Presence of at least 1 independently verified measurable brain metastasis in accordance with mRECIST (Appendix 1) that can be accurately assessed at baseline and suitable for accurate repeated measurements and with a tumor diameter of 0.5-3 cm on magnetic resonance imaging \[MRI\]).
- •Previous SRS and excision of up to 5 brain metastases are permitted at least 3 weeks prior to study treatment initiation, provided that neurologic sequelae have completely resolved and measurable untreated lesion(s) remain. If the patient had prior whole brain radiation therapy or SRS, progression in any measurable brain metastasis must have occurred at least 1 month after the end of radiation therapy for the irradiated lesion to be counted as measurable.
- •Patients can have asymptomatic (no neurologic signs or symptoms, not requiring immediate local intervention \[surgery or radiosurgery\] or systemic glucocorticoid therapy \[within 10 days prior to study treatment initiation\]) OR minimally symptomatic brain metastases (requiring ≤10 mg prednisone or equivalent per day and not requiring immediate surgical or radiation therapy in the opinion of the treating investigator and a radiation therapy or neurosurgical consultant).
- •Extracranial disease is not required and if present, it can be measurable or non-measurable (RECIST v1.1).
- •A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- •Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 OR
- •A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 during the treatment period and for at least 120 days after the last dose of study treatment.
- •A male patient must agree to use contraception as detailed in Appendix 6 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
Exclusion Criteria
- •Patients are excluded from the study if any of the following criteria apply, unless medically indicated and after approval by study chair/IRB office:
- •Has NSCLC with an oncogenic driver mutation (mutation\[s\] in EGFR, ERBB2, or BRAF V600E; fusion/rearrangement\[s\] in ALK, ROS1, NTRK, or RET; or MET amplification). KRAS or PIK3CA mutation are allowed.
- •Has hepatocellular carcinoma. NOTE: patients with hepatocellular carcinoma and brain metastasis are excluded from this trial because the dose of lenvatinib approved for this disease is different than the ones used in this trial.
- •Has symptomatic or untreated spinal cord compression. Patients with clinical or radiographic evidence of leptomeningeal metastases or other metastatic systemic disease are not allowed. In cases where brain metastases are superficially located (cortical-based brain metastasis) and leptomeningeal spread is suspected, a work-up for leptomeningeal disease (LMD) should be performed (MRI and lumbar puncture with CSF cytology). If LMD is not confirmed, the treating physician, neuro-oncologist, or brain metastasis multidisciplinary team should make a clinical call and exclude the patient if LMD dissemination is likely.
- •Has received prior therapy with lenvatinib or other antiangiogenic tyrosine kinase inhibitor alone or in combination with a PD-1/PD-L1 inhibitor. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD L2, or anti-CTLA-4 agent or chemotherapy is allowed.
- •Has received prior systemic anticancer therapy including investigational agents within 28 days prior to study treatment initiation.
- •Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Patients with ≤ Grade 2 neuropathy may be eligible. Patients with immunotherapy-related AEs of a permanent nature but manageable (hypothyroidism on thyroid hormone replacement, vitiligo, etc.) are eligible.
- •Patients must have recovered adequately from any complications from major surgery. Withhold lenvatinib treatment for at least 1 week prior to elective surgery. Do not administer lenvatinib for at least 2 weeks following major surgery and until adequate wound healing.
- •Has received radiotherapy within 14 days prior to study treatment initiation. Patients must have recovered from all radiation-related toxicities, not require corticosteroids in dosing exceeding 10 mg daily of prednisone equivalent, and not have had radiation pneumonitis. Any radiation to the brain or spinal cord/cauda equina must have been completed within \>3 weeks from study treatment initiation.
- •Has received a live vaccine or live-attenuated vaccine within 30 days prior to study treatment initiation. Administration of killed vaccines is allowed.
Arms & Interventions
Cohort 1
Patients with TNBC and brain metastases
Intervention: Pembrolizumab
Cohort 1
Patients with TNBC and brain metastases
Intervention: Lenvatinib
Cohort 3
Patients with other solid tumor types and brain metastases
Intervention: Lenvatinib
Cohort 2
Patients with NSCLC and brain metastases
Intervention: Pembrolizumab
Cohort 2
Patients with NSCLC and brain metastases
Intervention: Lenvatinib
Cohort 3
Patients with other solid tumor types and brain metastases
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
To establish the intracranial ORR of the pembrolizumab and lenvatinib combination in patients with TNBC or NSCLC and brain metastases, as assessed according to the modified RECIST
Time Frame: through study completion, an average of 1 year