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Cerebellar Ataxia

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Ataxia Telangiectasia

Colorectal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Intestinal Neoplasms

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Gastrointestinal Diseases

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Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients receive tuvusertib PO QD) on days 1-7 and temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI as well as collection of blood samples throughout the trial. Patients also undergo a biopsy at baseline and may undergo one on study and/or at time of progression.

Biopsy

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Tuvusertib

Site Public Contact

Shumei Kato

Michael Cecchini

Nikolaos Trikalinos

Raed Al-Rajabi

Abdul Rafeh Naqash

Janie Y. Zhang

This phase I/II trial studies the side effects and best dose of temozolomide and M1774 and how well they works in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and may have spread to nearby tissue, lymph nodes, or distant parts of the body (advanced). Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells and slow down or stop tumor growth. M1774 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Adding M1774 to temozolomide may shrink or stabilize cancer for longer than temozolomide alone.

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose of the combination of temozolomide (TMZ) and tuvusertib (M1774).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To determine the overall response rate. III. To estimate progression free survival. IV. To estimate overall survival. V. To determine the recommended phase 2 dose of the combination of TMZ and M1774.

EXPLORATORY OBJECTIVES:

I. Correlate MGMT promoter hypermethylation, MGMT expression and tumor-infiltrating lymphocytes (TILs) with efficacy endpoints of response rate, progression free survival, and overall survival.

II. Assess pre and post treatment tumor biopsies for changes in tumor mutational burden, tumor associated neo-antigens and microsatellite status by whole exome sequencing.

III. Measure changes in peripheral blood mononuclear cell populations with treatment.

IV. Assess liquid biopsies by circulating tumor (ct)DNA for changes in tumor mutational burden and microsatellite status by whole exome sequencing.

OUTLINE: This is a phase I, dose-escalation study of temozolomide and tuvusertib followed by a phase II study.

Patients receive tuvusertib orally (PO) once daily (QD) on days 1-7 and temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan and magnetic resonance imaging (MRI) as well as collection of blood samples throughout the trial. Patients also undergo a biopsy at baseline and may undergo one on study and/or time of progression.

After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months for up to 2 years.

Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness

A Phase 1/2 Trial Evaluating the Combination of Temozolomide and the Ataxia Telangiectasia and Rad3-Related Inhibitor M1774

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Defined as adverse events meeting the criteria that are at least "possibly related" to TMZ or M1774. Dose limiting toxicity for temozolomide in combination with M1774 and the maximum tolerated dose or maximum safe dose. Will consider ten dose levels (dose level -2, -1, 1, 2, 3, 4, 5, 6, 7, 8). The Bayesian Optimal Interval (BOIN) design based on the cumulative number of patients who experience a dose-limiting toxicity (DLT) at the current dose level will be used to guide dose escalation.

Will report the ORR and corresponding 2-sided 90% exact confidence intervals using the Clopper-Pearson method.

Will be estimated using Kaplan-Meier method. Median survival times will be estimated. The confidence intervals for the median will be calculated. Log-rank test will be used to compare the PFS between the MGMT+ and MGMT- group.

Will be estimated using Kaplan-Meier method. Median survival times will be estimated. The confidence intervals for the median will be calculated. Log rank test will be used to compare the OS between the MGMT+ and MGMT- group.

The revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.

National Cancer Institute (NCI)

Niraparib

Panitumumab

Antineoplastic Agents, Immunological

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive 200 or 300 mg niraparib orally once daily on days 1-28 and 6 mg/kg panitumumab intravenously over 60-90 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Olatunji Alese, MD

This phase II trial studies the side effects and how well niraparib and panitumumab work in treating patients with colorectal cancer that has spread to other places in the body. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving niraparib and panitumumab may work better in treating patients with colorectal cancer.

PRIMARY OBJECTIVE:

I. Evaluate the activity of the combination of niraparib with epidermal growth factor receptor (EGFR) inhibitor panitumumab in previously treated patients with rat sarcoma gene (RAS) wild type (WT) metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. Define the toxicity profile of the combination of niraparib and panitumumab.

II. Evaluate the activity of the combination of niraparib and panitumumab in previously treated patients with metastatic colorectal cancer.

OUTLINE:

Patients receive niraparib orally (PO) once daily (QD) on days 1-28 and panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 6 months for 2 years, and then annually for up to 5 years.

Niraparib and Panitumumab in Patients With Advanced or Metastatic Colorectal Cancer

A Phase II Study of Niraparib in Combination With EGFR Inhibitor Panitumumab in Patients With Advanced Colorectal Cancer

The efficacy, as measured by clinical benefit rate (CBR), will be assessed for the total number of patients enrolled. CBR = (Complete Response + Partial Response + Stable Disease \[CR +PR + SD\] rate. Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria using an independent review.

Objective response rate (ORR) is defined as the percentage of patients with complete response (CR) or partial response (PR), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria using an independent review.

Duration of response (DOR) is defined as the time from the initial response (complete response \[CR\] or partial response \[PR\]) until the time of first documentation of disease progression, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria using an independent review.

For progression free survival (PFS), progression or death from any cause will be defined as the event. Progression will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria using an independent review. Patients will be censored at time of last follow-up.

For overall survival (OS), death from any cause will be defined as the event. Patients will be censored at time of last follow-up.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness	NCT05691491	Advanced Malign... Advanced Micros... Hematopoietic a... Metastatic Mali... Metastatic Micr... Stage III Color... Stage IV Colore...	Biopsy Biospecimen Col... Computed Tomogr... Magnetic Resona... Temozolomide Tuvusertib	18 Years -	National Cancer Institute (NCI)
Niraparib and Panitumumab in Patients With Advanced or Metastatic Colorectal Cancer	NCT03983993	Advanced Micros... Metastatic Micr... Microsatellite ... RAS Wild Type Stage IV Colore... MSI-H Colorecta...	Niraparib Panitumumab	18 Years -	Emory University

Spots Global Cancer Trial Database for advanced microsatellite stable colorectal carcinoma