Tepotinib with or without Osimertinib for the Treatment of Brain Tumors and Non-small Cell Lung Cancer in Patients with Genetic Mutations
This phase I trial tests the safety, side effects, and best dose of tepotinib with or without osimertinib in treating patients with brain tumors and non-small cell lung cancer with different genetic mutations. Tepotinib and osimertinib are in a class of medications called kinase inhibitors. They work by blocking the action of abnormal proteins that signal tumor cells to multiply. This helps slow or stop the spread of tumor cells. Giving tepotinib alone may help control disease in patients with A) cancer that has spread to the brain (brain metastasis) and mutations in the MET gene, and B) glioblastoma (a type of primary brain cancer) that has come back after treatment (recurrent) and mutations in the MET gene. Giving tepotinib and osimertinib together may help control disease in patients with non-small cell lung cancer and brain metastasis that is resistant to a type of chemotherapy called EGFR-TKIs, and mutations in the EGFR gene.
Inclusion Criteria
- Willing and able to provide written informed consent for the trial.
- >= 18 years of age on day of signing informed consent
- Performance status of > 60 on the KPS (Karnofsky Performance Status) scale, or ECOG (Eastern Cooperative Oncology Group) performance score of 0 or 1
- Magnetic resonance imaging (MRI) of the brain consistent with either new or progressive brain metastasis or recurrent glioblastoma
- Group A: Histologically-confirmed primary cancer or brain metastasis with MET alteration identified through molecular testing
- Group B: Histologically-confirmed World Health Organization (WHO) grade IV glioma (glioblastoma or gliosarcoma) with MET alteration identified through molecular testing. * Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of grade IV glioma is made at some point along the disease trajectory. * Note: Patients with IDH wildtype grade III anaplastic astrocytoma (1p19q intact) are also eligible, as these tumors are expected to behave similarly to grade IV glioma. * At first, second or third recurrence of glioblastoma, and patients must have received prior radiation and/or chemotherapy.
- Group C: NSCLC with documented activating mutation of the EGFR receptor including T790M status, and with acquired resistance on previous EGFR-TKI therapy, and MET alteration identified through molecular testing. * Patients must have radiological documentation of disease progression on previous EGFR-TKI therapy. * Patients may have received osimertinib. If brain mets progression occurs on osimertinib, patient will be eligible if continues osimertinib.
- Phase 1b, Group A: Patients must have NSCLC (confirmed by either histology or cytology) with documented METexon14-skipping mutations identified in primary or brain metastasis tissue and/or in circulating tumor DNA in plasma (liquid biopsy)
- Phase 1a, Groups A and B participants must require surgical resection for clinical care. * Phase 1a, Group A: Patient must be surgical candidate for brain metastasis (solitary met, single met > ~ 2 cm (surgeon’s discretion), multiple mets but one large met, symptomatic met controlled on steroid, and/or highly radioresistant met), but not require immediate surgery. * Phase 1a, Group B: Patient must be surgical candidate for glioblastoma, as determined by treating physician, but not require immediate surgery
- Phase 1a, Group C and Phase 1b, Groups A and C participants must have small, minimally symptomatic/asymptomatic brain metastasis that do not require surgical resection
- Measurable disease * Groups A and C: Presence of at least 1 independently verified measurable brain metastasis in accordance with a modified RANO-BM that can be accurately assessed at baseline with >= 5 mm* in the longest diameter with MRI, which is suitable for accurate repeated measurements and that preferably was not previously irradiated or biopsied *and must be surgical candidate * Group B: Presence of measurable glioblastoma, per RANO criteria, and that can be accurately assessed at baseline with >= 5 mm* in the longest diameter with MRI, which is suitable for accurate repeated measurements *and must be surgical candidate
- Willing to undergo CSF sampling via lumbar puncture
- No medical contraindication to lumbar puncture (to include severe coagulopathy, radiographic concern for impending herniation or obstructive hydrocephalus, or soft tissue infection at puncture site, as outlined in MD Anderson institutional policy). * Patient may still enroll but lumbar puncture (LP) may be deferred if at any time the treating physician determines that it would be unsafe to perform this procedure due to the characteristics (size, associated edema, etc) of the brain tumor
- If taking steroids, stable or decreasing dose of steroids for at least 5 days prior to enrollment; no more than 4 mg dexamethasone (or equivalent) total per day for patients with brain metastasis, and no more than 8 mg per day for patients with glioblastoma
- Absolute neutrophil count (ANC) >=1,500 /mcL (performed within 14 days prior to registration)
- Platelets >= 100,000 / mcL (performed within 14 days prior to registration)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 14 days prior to registration)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) (performed within 14 days prior to registration) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for participant with creatinine levels > 1.5 X institutional ULN (performed within 14 days prior to registration)
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 ULN (performed within 14 days prior to registration)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for participants with liver metastases (performed within 14 days prior to registration)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless participant is receiving anticoagulant therapy; as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration)
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration)
- Female patients of childbearing potential should have a negative serum pregnancy test.
- Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity, for the course of the study through 28 days after the last dose of study medication. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 28 days after the last dose of study therapy.
- For patients with brain mets, if patient had prior whole-brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS), progression in any measurable brain metastasis must have occurred at least 1 month after the end of radiation therapy.
- First day of study drug must be more than 2 weeks from last day of any radiation to the brain or spinal cord/cauda equina
- Patients with minimally symptomatic brain metastases may be enrolled without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant
Exclusion Criteria
- Currently participating in or has participated in a study of an investigational agent (with the exception of participating in which the investigational agent was a 1st, 2nd, or 3rd generation EGFR-TKI) within 4 weeks prior to study enrollment
- Any unresolved toxicity Grade 2 or higher according to National Cancer Institute (NCI)-CTCAE version 5, from previous anticancer therapy, with the exception of alopecia
- Need for transfusion within 14 days prior to enrollment
- Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
- Active infection requiring systemic therapy
- History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 28 days after the last dose of trial treatment
- History of interstitial lung disease (ILD) or interstitial pneumonitis including radiation pneumonitis that required steroid treatment
- Impaired cardiac function: * Left ventricular ejection fraction < 45% defined by echocardiography * Serious arrhythmia * Unstable angina pectoris * Congestive Heart Failure New York Heart Association III and IV * Myocardial infarction, stroke, or transient ischemic attack within the last 6 months prior to study entry. * Corrected QT interval (Fridericia's correction formula [QTcF]) > 470 ms for women and > 450 ms for men at screening. * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives, or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
- Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg).
- Group C: Contraindication to the administration of osimertinib
- Medical history of liver fibrosis/cirrhosis
- Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product
- Known human immunodeficiency virus positivity
- Group C: Has not received an EGFR-TKI containing treatment prior to enrollment into the study
- Prior treatment with other agents targeting the HGF/MET pathway such as crizotinib, capmatinib, savolitinib, foretinib, glesatinib, cabozantinib, merestinib, onartuzumab, rilotumumab, emibetuzumab, and ficlatuzumab
- Participants currently receiving (or unable to stop use at least 1 week prior to enrollment) medications or herbal supplements known to be potent inducers of CYP3A4
Additional locations may be listed on ClinicalTrials.gov for NCT05120960.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) of tepotinib hydrochloride (tepotinib) for patients with brain metastasis and MET alterations. (Group A) (Phase Ia)
II. To determine RP2D of tepotinib in patients with GLIOBLASTOMA with MET alterations. (Group B) (Phase Ia)
III. To determine RP2D of tepotinib in combination with osimertinib mesylate (osimertinib) in patients with EGFR positive (+) non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitor (TKI) resistance and MET amplification. (Group C) (Phase Ia)
IV. To determine intracranial clinical benefit of tepotinib in brain metastases (mets), as measured by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM), in patients with non-small cell lung cancer (NSCLC) and METex14-skipping mutations. (Group A) (Phase Ib)
V. To determine intracranial clinical benefit of tepotinib in combination with osimertinib, in brain metastasis, as measured by RANO-BM, in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification. (Group C) (Phase Ib)
SECONDARY OBJECTIVES:
I. To evaluate the safety and toxicity of tepotinib in treating brain metastasis in patients with MET alterations in Group A, as measured by Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. (Phase Ia)
II. To evaluate the pharmacokinetic/pharmacodynamic (PK/PD) (including phosphomet level) of tepotinib in brain metastasis tissue and cerebrospinal fluid (CSF) in patients with MET alterations in Group A. (Phase Ia)
III. To determine overall survival in Group A. (Phase Ia)
IV. To determine progression-free survival for intracranial disease and extracranial disease in Group A. (Phase Ia)
V. To determine intracranial objective response rate according to RANO-BM and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [Qianet al., 2017] of Group A. (Phase Ia)
VI. To determine extracranial objective response rate as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 of Group A. (Phase Ia)
VII. To identify the site of first progression (intracranial vs extracranial) in Group A. (Phase Ia)
VII. To identify the site of first progression (intracranial versus [vs] extracranial) in Group A. (Phase Ia)
VIII. To determine the duration of intracranial response by BM-RANO and by mRECIST in Group A. (Phase Ia)
IX. To determine the duration of extracranial response by RECIST 1.1 in Group A. (Phase Ia)
X. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group A. (Phase Ia)
XI. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) and European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) questionnaires in Group A. (Phase Ia)
XII. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group A. (Phase Ia)
XIII. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group A. (Phase Ia)
XIV. To evaluate the safety and toxicity of tepotinib in treating glioblastoma in patients with MET alterations (Group B), as measured by CTCAE, version 5.0. (Phase Ia)
XV. To evaluate the PK/PD (including phosphomet level) of tepotinib in glioblastoma tissue and CSF in patients with MET alterations in Group B. (Phase Ia)
XVI. To determine survival (progression-free survival [PFS], overall survival [OS]) of Group B. (Phase Ia)
XVII. To determine objective response rate according to RANO of Group B. (Phase Ia)
XVIII. To determine the duration of response by RANO in Group B. (Phase Ia)
XIX. To determine the time to progression (defined as progression of existing lesions and development of new lesions) in Group B. (Phase Ia)
XX. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group B. (Phase Ia)
XXI. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group B. (Phase Ia)
XXII. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group B. (Phase Ia)
XXIII. To evaluate the safety and toxicity of the combination of osimertinib and tepotinib in treating patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification, with (Group C), as measured by CTCAE, version 5.0. (Phase Ia)
XXIV. To evaluate the PK/PD (including phosphomet level) of tepotinib in CSF in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification treated with the combination of osimertinib and tepotinib. (Group C) (Phase Ia)
XXV. To determine overall survival in Group C. (Phase Ia)
XXVI. To determine progression-free survival for intracranial disease and extracranial disease in Group C. (Phase Ia)
XXVII. To determine intracranial objective response rate according to RANO-BM and mRECIST of Group C. (Phase Ia)
XXVIII. To determine extracranial objective response rate as assessed by RECIST v1.1 for Group C. (Phase Ia)
XXIX. To identify the site of first progression (intracranial vs extracranial) in Group C. (Phase Ia)
XXX. To determine the duration of intracranial response by BM-RANO and by mRECIST in Group C. (Phase Ia)
XXXI. (Phase Ia) To determine the duration of extracranial response by RECIST 1.1 in Group C. (Phase Ia)
XXXII. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group C. (Phase Ia)
XXXIII. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group C. (Phase Ia)
XXIV. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group C. (Phase Ia)
XXXV. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group C. (Phase Ia)
XXXVI. To evaluate the safety and toxicity of tepotinib as measured by CTCAE, version 5.0 in patients with NSCLC and METex14-skipping mutations. (Group A) (Phase 1b)
XXXVII. To evaluate the PK/PD (including phosphomet level) of tepotinib in the CSF in patients with NSCLC and METex14-skipping mutations. (Group A) (Phase 1b)
XXXVIII. To determine overall survival in Group A. (Phase 1b)
XXXIX. To determine progression-free survival for intracranial disease and extracranial disease in Group A. (Phase 1b)
XL. To determine intracranial objective response rate according to RANO-BM and mRECIST of Group A. (Phase 1b)
XLI. To determine extracranial objective response rate as assessed by RECIST v1.1 of Group A. (Phase 1b)
XLII. To identify the site of first progression (intracranial vs extracranial) in Group A. (Phase 1b)
XLIII.To determine the duration of intracranial response by BM-RANO and by mRECIST in Group A. (Phase 1b)
XLIV. To determine the duration of extracranial response by RECIST 1.1 in Group A. (Phase 1b)
XLV. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group A
XLVI. (Phase 1b) To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group A
XLVII. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group A. (Phase 1b)
XLVIII. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group A. (Phase 1b)
XLIX. To evaluate the safety and toxicity as measured by CTCAE, version 5.0, in patients with EGFR+ NSCLC with EGFR TKI resistance and MET amplification (Group C)
L. To evaluate the PK/PD (including phosphomet level) of tepotinib in CSF in patients with EGFR TKI resistance and MET amplification (Group C) (Phase 1b)
L!. To determine overall survival in Group C. (Phase 1b)
LII. To determine progression-free survival for intracranial disease and extracranial disease in Group C. (Phase 1b)
LIII. To determine intracranial objective response rate according to RANO-BM and mRECIST of Group C. (Phase 1b)
LIV. To determine extracranial objective response rate as assessed by RECIST v1.1 for Group C. (Phase 1b)
LV. To identify the site of first progression (intracranial vs extracranial) in Group C. (Phase 1b)
LVI. To determine the duration of intracranial response by BM-RANO and by mRECIST in Group C. (Phase 1b)
LVII. To determine the duration of extracranial response by RECIST 1.1 in Group C. (Phase 1b)
LVIII. To determine the time to intracranial progression (defined as progression of existing lesions and development of new lesions) in Group C. (Phase 1b)
LVIX. To explore the patient experience with treatment using patient-reported outcomes (PROs) using the MDASI-BT and EQ-5D-5L questionnaires in Group C. (Phase 1b)
LX. To identify the frequency of grade 3+ toxicities at 4 weeks, and 3, 6, 9, 12 and 18 months in Group C. (Phase 1b)
LXI. To determine changes in dose, duration and frequency of steroid use for symptomatic management in Group C. (Phase 1b)
CORRELATIVE OBJECTIVES:
I. Assess circulating tumor deoxyribonucleic acid (ctDNA) in CSF in all participants, and explore relationship to matched blood and tissue samples, when available.
II. Explore pharmacodynamic relationships for safety and/or efficacy endpoints, when possible.
III. Explore biomarkers of response and resistance in CSF specimens prior to exposure to drug, during exposure to drug, and at the time of disease progression.
IV. Pursue whole exome sequencing (WES) additional genomic evaluation of available brain tumor tissue samples.
V. Run ribonucleic acid sequencing (RNAseq) for gene expression profiling in available brain tumor tissue samples.
OUTLINE: This is a phase Ia, dose-escalation study of tepotinib followed by a phase Ib dose-expansion study.
PHASE 1A: Patients are assigned to 1 of 3 groups.
GROUP A: Patients with brain mets able to be removed by surgery (resectable) and MET gene mutation receive tepotinib orally (PO) once daily (QD) or twice daily (BID). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients with resectable recurrent glioblastoma and MET gene mutation receive tepotinib PO QD or BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
GROUP C: Patients in this group must have: 1) Newly-diagnosed or recurrent brain mets or EGFR gene-mutated NSCLC; and 2) EGFR-TKI resistance and MET gene amplification. Patients receive tepotinib PO QD and osimertinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
PHASE 1B: Patients are assigned to 1 of 2 groups.
GROUP A: Patients with NSCLC brain mets and MET exon 14 deletion mutation receive tepotinib PO QD or BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients in this group must have: 1) Newly-diagnosed or recurrent brain mets or EGFR gene-mutated NSCLC; and 2) EGFR-TKI resistance and MET gene amplification. receive tepotinib PO daily or twice daily and osimertinib PO daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, all patients are followed up at 90 days. Patients completing study treatment for any reason other than disease progression are followed every 8 weeks until confirmed disease progression. Patients with disease progression are followed every 12 weeks for up to 2 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorBarbara Jane O'Brien
- Primary ID2021-0281
- Secondary IDsNCI-2021-12845
- ClinicalTrials.gov IDNCT05120960