Temodar Plus Tyrosine Kinase Inhibitors for Progressive CNS Disease

NCT04541407 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 20-0138.ccNCI-2020-13878
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This trial is testing two novel combinations (temozolomide plus osimertinib OR temozolomide plus lorlatinib) which have not been evaluated in clinical trials. Thus, the exact benefits of these novel combinations are unclear. However, based on the mechanism of action of temozolomide and CNS(Central Nervous System) penetration/activity in other tumor types, it is hypothesized that adding temozolomide to osimertinib or temozolomide to lorlatinib may provide improvement in CNS disease control in patients with CNS progression on either of these latter two TKIs (Tyrosine kinase inhibitors).

Conditions

Non Small Cell Lung Cancer; CNS Progression

Outcome Measures

Primary Outcomes (1)

• Adverse events

  Adverse events will be determined by the common terminology criteria for adverse events version 5.0

  Up to 3.5 years

Secondary Outcomes (8)

• CNS response rate

  Up to 3.5 years

• Extra-CNS response rate

  Up to 3.5 years

• Overall response rate

  Up to 3.5 years

• Incidence of improvement in neurological function

  Up to 3.5 years

• Progression free survival (PFS)

  Up to 3.5 years

Study Arms (2)

Exon 19 deletions or L858R point mutations in exon 21

EXPERIMENTAL

Will include patients with exon 19 deletions or L858R point mutations in exon 21 of the epidermal growth factor receptor (EGFR) gene. Temozolomide plus Osimertinib will be the study drug combination administered. Osimertinib will be given at a fixed dose of 80 mg daily for dose level 1, with a potential to increase to 160 mg daily for dose level 2. Temozolomide will be started at a dose of 150 mg/m2 on days 1-5 of a 28 day cycle for cycle 1 and if tolerated will be increased to 200 mg/m2 on days 1-5 of a 28 day cycle for cycles 2+. There will be a -1 dose level.

Drug: Temozolomide plus Osimertinib

Patients with anaplastic lymphoma kinase (ALK) fusions

EXPERIMENTAL

Will include patients with anaplastic lymphoma kinase (ALK) fusions. Temozolomide plus Lorlatinib will be the study drug combination administered. Lorlatinib will be given at a fixed dose of 100 mg daily. Temozolomide will be started at a dose of 150 mg/m2 on days 1-5 of a 28 day cycle for cycle 1 and if tolerated will be increased to 200 mg/m2 on days 1-5 of a 28 day cycle for cycles 2+. There will be a -1 dose level depending on tolerability.

Drug: Temozolomide plus Lorlatinib

Interventions

Temozolomide plus Osimertinib DRUG

Temozolomide is an oral alkylating chemotherapy which has good CNS penetration and has demonstrated CNS responses in both primary brain tumors (e.g., glioblastoma and anaplastic astrocytoma) and in small cell lung cancer (SCLC) brain metastases. Preclinical data from glioblastoma suggests potential synergy of concurrent ALK or EGFR inhibition with temozolomide and early phase trials in glioblastoma are ongoing investigating such combinations. It is felt that combining temozolomide with osimertinib or lorlatinib may be beneficial for patients with progressive CNS disease on either of these TKIs because of the high CNS penetration of temozolomide, good CNS activity of temozolomide in other tumor types and preclinical data from glioblastoma suggesting a potential enhanced effect of concurrent EGFR and ALK/ROS1 inhibition with temozolomide.

Exon 19 deletions or L858R point mutations in exon 21

Temozolomide plus Lorlatinib DRUG

Temozolomide is an oral alkylating chemotherapy which has good CNS penetration and has demonstrated CNS responses in both primary brain tumors (e.g., glioblastoma and anaplastic astrocytoma) and in small cell lung cancer (SCLC) brain metastases. Preclinical data from glioblastoma suggests potential synergy of concurrent ALK or EGFR inhibition with temozolomide and early phase trials in glioblastoma are ongoing investigating such combinations. It is felt that combining temozolomide with osimertinib or lorlatinib may be beneficial for patients with progressive CNS disease on either of these TKIs because of the high CNS penetration of temozolomide, good CNS activity of temozolomide in other tumor types and preclinical data from glioblastoma suggesting a potential enhanced effect of concurrent EGFR and ALK/ROS1 inhibition with temozolomide

Patients with anaplastic lymphoma kinase (ALK) fusions

Eligibility Criteria

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

You may qualify if:

• Provision to sign and date the consent form.
• Stated willingness to comply with all study procedures and be available for the duration of the study.
• Male or female subject ≥ 18 years old
• ECOG performance status 0-2
• Stage IV NSCLC with progression of disease in the CNS on osimertinib 80 mg daily for patients with EGFR activating mutations (EGFR exon 19 deletions or EGFR L858R exon 21 point mutations) -OR- Stage IV NSCLC with progression of disease in the CNS on lorlatinib 100 mg daily for patients with ALK fusions
• Evaluable CNS disease is required, measurable CNS disease is not required
• Patients who are on corticosteroids must be on stable or decreasing doses of corticosteroids for at least 14 days.
• Adequate hematologic function defined as:
• ANC ≥ 1.5 x 10\^9/L
• Hemoglobin ≥ 9 g/dL
• Platelets ≥ 150 x 10\^9/L
• Adequate hepatic function defined as:
• Total bilirubin ≤1.5 x upper limit of normal (ULN). For subjects with Gilbert's Disease, Total bilirubin ≤3 x ULN
• ALT and AST ≤3 x ULN. For subjects with documented liver metastases, ALT and AST ≤5×ULN
• Adequate renal function defined as:

You may not qualify if:

• Patients with compound mutations in EGFR will be excluded from this study. Compound mutations are defined as 2 or more mutations in the EGFR tyrosine kinase domain with the following exceptions:
• C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and
• T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation.
• Prior therapy with temozolomide.
• Patients must not receive surgery or radiation as local therapies for the progressing CNS disease for which they are being enrolled on this trial. Ventriculoperitoneal shunt placement will be allowed for leptomeningeal disease with symptomatic hydrocephalis. Radiation or surgery for progressing extra-CNS disease is allowed.
• Patients with a history of an allergic/hypersensitivity reaction to any component of temozolomide, dacarbazine, osimertinib (for temozolomide plus osimertinib arm) or lorlatinib (for temozolomide plus lorlatinib arm).
• Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia.
• Patients with a history of baseline QTcF interval greater than 470 msec on electrocardiogram for the osimertinib plus temozolomide arm only.
• Unstable or clinically significant concurrent medical condition, psychiatric illness or social situation that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
• Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy. Suppressive therapy for chronic infections allowed, for example:
• Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed. Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy.
• Treated with any investigational drug or chemotherapy within 3 weeks or ≤ 5 half-lives of first dose of study treatment.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.
• Patient is not taking any prohibited medications listed in section 6.4. (Strong CYP3A inducers should be stopped greater than 3 half-lives prior to starting study drugs for patients on either study drug combination. Moderate inducers of CYP3A should be stopped greater than 3 half-lives prior to starting study drugs for patients receiving lorlatinib plus temozolomide. Strong CYP3A inhibitors should be stopped greater than 3 half-lives prior to starting study drugs for patients receiving lorlatinib plus temozolomide.)

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Cancer League of Colorado: collaborator

Study Sites (1)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Temozolomide; osimertinib; lorlatinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Jose E Pacheco

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: This is a phase I, 3 + 3 dose escalation study of Temozolomide plus osimertinib, and temozolomide plus lorlatinib. The two drug combinations will each be examined separately in the 3 + 3 dose escalation schema to determine the MTD(Maximum tolerated dose) and RP2D(Recommended phase 2 dose).

Study Record Dates

• First Submitted: September 1, 2020
• First Posted: September 9, 2020
• Study Start: October 29, 2020
• Primary Completion: April 25, 2022
• Study Completion: June 7, 2022
• Last Updated: May 16, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)