A Phase 1a/1b Study to Determine the Recommended Phase 2 Dose, of Tepotinib in Participants With MET Alterations and Brain Tumors

NCT05120960 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 2021-0281NCI-2021-12845
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a single center, multi-arm, biomarker-driven phase 1 study to assess the RP2D, PK/PD, safety, and activity of tepotinib in participants with MET alterations and brain tumors. Eligible patients include those with brain metastases or glioblastoma, including patients who are surgical candidates. In patients with EGFR+ NSCLC with EGFR-TKI resistance and MET amplification, tepotinib will be given in combination with osimertinib. This phase 1 study will be conducted in 2 parts, Phase 1a (dose exploration) and Phase 1b (dose expansion). Phase 1a will include a surgical resection window of opportunity component. Phase 1b (dose expansion) can open once the relevant RP2D has been estimated in Phase 1a (dose exploration). Phase 1a (Dose Exploration): Patients will be assigned to dose levels within a Group as outlined in the Statistical Analysis Plan. Group A will be comprised of patients who are surgical resection candidates with newly-diagnosed or recurrent brain metastases and MET alteration. Group B will be comprised of patients who are surgical resection candidates with recurrent glioblastoma and MET alteration. Group C will be comprised of patients with newly-diagnosed or recurrent brain metastases and epidermal growth factor receptor mutated (EGFR+) non-small cell lung cancer (NSCLC). Phase 1b (Dose Expansion): Upon completion of the Phase 1a (dose exploration) component and estimation of a RP2D, dose expansion may proceed within Group A (consisting of patients with brain metastasis and MET alteration) and Group C (EGFR+ NSCLC brain metastasis, TKI resistance, and MET amplification). Dose expansion in these 2 groups may be done concurrently, but enrollment in each group does not require completion of the entire Phase 1a component of the study. There will not be a Group B (glioblastoma) in Phase 1b. Patients in Phase 1b will not undergo surgical resection.

Conditions

Brain Tumor

Outcome Measures

Primary Outcomes (1)

• To determine the recommended phase II dose (RP2D) of tepotinib for patients with brain metastasis and MET alterations (Group A)

  through study completion, an average of 1 year

Study Arms (2)

Group A

EXPERIMENTAL

will receive tepotinib alone

Drug: tepotinib

Group B

EXPERIMENTAL

will receive tepotinib and osimertinib

Drug: tepotinib; Drug: tepotinib plus osimertinib

Interventions

tepotinib DRUG

Given by PO

Group A; Group B

tepotinib plus osimertinib DRUG

Given by PO

Group B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible for participation in this trial, the participant must:
• Willing and able to provide written informed consent for the trial.
• 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.
• 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: Histiologically-confirmed 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 histiological 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 elgibile, 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.
• a. Patients must have radiological documentation of disease progression on previous EGFR-TKI therapy.
• b. 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.

You may not qualify if:

• \. 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 NCI-CTCAE version 5, from previous anticancer therapy, with the exception of alopecia. 3. Need for transfusion within 14 days prior to enrollment. 4. 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. 6. 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 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 (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).

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Related Links

• M D Anderson Cancer Center

MeSH Terms

Conditions

Brain Neoplasms

Interventions

tepotinib; osimertinib

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Barbara O'Brien, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2021
• First Posted: November 16, 2021
• Study Start: February 27, 2023
• Primary Completion: April 12, 2024
• Study Completion: April 12, 2024
• Last Updated: April 17, 2024

Record last verified: 2024-04