Colorectal CancerPhase 2NCT04166435
TMZ + Olaparib for MGMT Hypermethylated Colorectal Cancer
A Phase 2 study testing Temozolomide + Olaparib in people with Colorectal Cancer, run by Yale University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Cancer
- What is being tested?
- Temozolomide + Olaparib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Jun 2020to 12 Jun 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker research, patients must fulfill the following criteria:
- 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.
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- 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 :
- Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)° / serum creatinine (mg/dL) x 72
- where F=0.85 for females and F=1 for males.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Patients must have a life expectancy ≥ 16 weeks.
- At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.
- Postmenopausal is defined as:
- Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
- Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
- radiation-induced oophorectomy with last menses >1 year ago
- chemotherapy-induced menopause with >1 year interval since last menses
- surgical sterilisation (bilateral oophorectomy or hysterectomy)
- Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception ([see appendix C for acceptable methods]) if they are of childbearing potential.
Who cannot join
- 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.
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- 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.
- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib and temozolomide is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
- Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
- Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria related to "Patients must have had recurrence, progression or intolerance to standard therapy...").
- Participation in another clinical study with an investigational product administered in the last 28 days.
- Subjects with a known hypersensitivity to temozolomide, olaparib, any of the recipients of either product, or the combination.
- Patients with a known hypersensitivity to the combination/comparator agent.
- Involvement in the planning and/or conduct of the study
- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
- Previous enrollment in the present study.
- Breast feeding women.
Trial locations and contacts
1 site in 1 country.
United States1 site
Yale New Haven Hospital
New Haven, Connecticut, 06512
About this study
Official title: Temozolomide and Olaparib for O6-Methylguanine DNA Methyltransferase Promoter Hypermethylated Colorectal Cancer
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.
Read the detailed description
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. Patients will receive temozolomide orally daily on days 1-7 and olaparib twice daily continuously. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatments patients are followed up at 30 days, and for patients that come off treatment for reasons other than disease progression, clinical assessments will continue every 6 weeks for the first year and every 12 weeks after the first year.
PRIMARY OBJECTIVES:
- To determine the efficacy of TMZ in combination with olaparib in subjects with MGMT promoter hypermethylated advanced colorectal cancer by the overall response rate.
SECONDARY OBJECTIVES:
- To determine the safety of TMZ in combination with olaparib. II. To estimate the progression free survival (PFS). III. To estimate overall survival (OS).
EXPLORATORY OBJECTIVES:
- Characterize NGS profiling, patterns of DNA methylation, gene expression, and develop MGMT expression assays.
II. Correlate molecular features with Gamma H2AX with response. III. Establish organoids for MGMT promoter hypermethylated colorectal cancer.
- Conditions
- Colorectal Cancer
- Being tested
- Temozolomide + Olaparib
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Temozolomide + OlaparibDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Temozolomide + Olaparib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 1.5 years
Secondary outcomes (3)
Count of Participants With Adverse Events Greater or Equal to 3
To determine the safety of TMZ in combination with olaparib, the number of participants with ≥ grade 3 treatment related adverse events by CTCAE v5.0 coding will be assessed.
Measured: Up to 2 years from last treatment
Progression Free Survival
To estimate the progression free survival (PFS), patients will be followed for up to 24 months.
Measured: Up to 2 years from last treatment
Overall Survival
To estimate overall survival (OS), patients will be followed for up to 24 months.
Measured: Up to 2 years from last treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2019
- Study start17 Jun 2020
- Primary completion6 Jan 2022
- Study completion12 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Colorectal CancerStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Michael Cecchini, MD, Principal investigator, Assistant Professor of Medicine (Medical Oncology) Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04166435
- Sponsor's protocol ID
- 2000026632
- Status last verified
- Aug 2023
- First submitted
- 14 Nov 2019
- Last updated
- 6 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Temozolomide and Olaparib for O6-Methylguanine DNA Methyltransferase Promoter Hypermethylated Colorectal Cancer
- ClinicalTrials.gov ID
- NCT04166435
- Acronym / sponsor ID
- 2000026632
- Conditions
- Colorectal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- 17 Jun 2020 (actual)
- Primary completion
- 6 Jan 2022 (actual)
- Study completion
- 12 Jun 2023 (actual)
- First posted
- 18 Nov 2019 (actual)
- Results
- Posted 30 Jan 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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. Patients will receive temozolomide orally daily on days 1-7 and olaparib twice daily continuously. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatments patients are followed up at 30 days, and for patients that come off treatment for reasons other than disease progression, clinical assessments will continue every 6 weeks for the first year and every 12 weeks after the first year.
PRIMARY OBJECTIVES:
- To determine the efficacy of TMZ in combination with olaparib in subjects with MGMT promoter hypermethylated advanced colorectal cancer by the overall response rate.
SECONDARY OBJECTIVES:
- To determine the safety of TMZ in combination with olaparib. II. To estimate the progression free survival (PFS). III. To estimate overall survival (OS).
EXPLORATORY OBJECTIVES:
- Characterize NGS profiling, patterns of DNA methylation, gene expression, and develop MGMT expression assays.
II. Correlate molecular features with Gamma H2AX with response. III. Establish organoids for MGMT promoter hypermethylated colorectal cancer.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Temozolomide + Olaparib | Experimental | Drug: Temozolomide + OlaparibTemozolomide (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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (29 listed)
- 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.
- For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker research, patients must fulfill the following criteria:
- 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.
Key exclusion criteria (26 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Temozolomide + OlaparibTemozolomide (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 |
Primary outcome
Overall Response Rate
Time frame: Up to 1.5 years
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.
3 secondary outcomes
Count of Participants With Adverse Events Greater or Equal to 3
Time frame: Up to 2 years from last treatment
Progression Free Survival
Time frame: Up to 2 years from last treatment
Overall Survival
Time frame: Up to 2 years from last treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Sep 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Cecchini, MD principal investigator
Assistant Professor of Medicine (Medical Oncology) Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Temozolomide + Olaparib in people with Colorectal Cancer, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 29 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Jan 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Response Rate (time frame: Up to 1.5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Sep 2023.