TMZ + Olaparib for MGMT Hypermethylated Colorectal Cancer

NCT04166435 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 2000026632
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase II, non-randomized, open-label study to evaluate temozolomide in combination with olaparib in patients with MGMT promoter hypermethylated advanced colorectal cancer.

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate

  To determine the efficacy of TMZ in combination with olaparib in subjects with MGMT promoter hypermethylated advanced colorectal cancer. The overall response rate (ORR) was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) before and after treatment. Complete Response (CR): disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD). Clinical Benefit is defined as the sum of CR, PR, or SD post treatment from the start of treatment.

  Up to 1.5 years

Secondary Outcomes (3)

• Count of Participants With Adverse Events Greater or Equal to 3

  Up to 2 years from last treatment

• Progression Free Survival

  Up to 2 years from last treatment

• Overall Survival

  Up to 2 years from last treatment

Study Arms (1)

Temozolomide + Olaparib

EXPERIMENTAL

Temozolomide (75 mg/m2 orally on days 1-7 every 3 weeks) + Olaparib (150 mg orally twice daily days 1-21) in a 21-day cycle.

Drug: Temozolomide + Olaparib

Interventions

Temozolomide + Olaparib DRUG

Temozolomide (75 mg/m2 orally on days 1-7 every 3 weeks) + Olaparib (150 mg orally twice daily days 1-21) in a 21-day cycle.

Temozolomide + Olaparib

Eligibility Criteria

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

You may qualify if:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
• Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
• Provision of informed consent for genetic research prior to collection of sample
• Provision of informed consent for biomarker research prior to collection of sample \*\*If a patient declines to participate in the optional exploratory genetic research or the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.
• Individuals who are healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• Individuals with histologically proven relapsed/refractory mismatch repair proficient / microsatellite stable metastatic colorectal adenocarcinoma.
• MGMT promoter hypermethylation on pre-screening.
• Patients must have had recurrence, progression or intolerance to standard therapy consisting of at least 2 prior standard regimens (containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for metastatic disease. In the case where all chemotherapy agents are used concurrently (I.e. FOLFOXIRI +/- Bevacizumab) 1 prior treatment regimen is acceptable after discussion with the principal investigator. Relapse within 6 months of completing adjuvant chemotherapy is considered one line of therapy in the metastatic setting.
• Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
• Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN.
• Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test :

You may not qualify if:

• Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• Patients with known active hepatitis (i.e. Hepatitis B or C).
• Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Any previous treatment with PARP inhibitor, including Olaparib.
• Any previous treatment with temozolomide or other monofunctional alkylating agent.
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib and temozolomide is 2 weeks.

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale New Haven Hospital

New Haven, Connecticut, 06512, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Temozolomide; olaparib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. Michael Cecchini
• Organization: Yale University

michael.cecchini@yale.edu

(203) 737-3472

Study Officials

• Michael Cecchini, MD

  Assistant Professor of Medicine (Medical Oncology) Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2019
• First Posted: November 18, 2019
• Study Start: June 17, 2020
• Primary Completion: January 6, 2022
• Study Completion: June 12, 2023
• Last Updated: September 6, 2023
• Results First Posted: January 30, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)