Phase Ib/II study of M3814 in combination with capecitabine and radiotherapy in rectal cancer
- Conditions
- ocally advanced rectal cancerMedDRA version: 20.0Level: PTClassification code 10038038Term: Rectal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-002275-18-IT
- Lead Sponsor
- MERCK KGAA
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 150
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are >= 18 years of age, at the time of signing the informed consent
Type of Participant and Disease Characteristics
2. Have an Eastern Cooperative Oncology Group Performance Status <= 1
3. Have histologically confirmed and localized resectable rectal cancer (Stage II or Stage III at original staging). Participants who received induction chemotherapy are allowed to be enrolled to
this study except if this induction is resulting in complete response (as per tumor evaluation charter).
4. Have lower edge of the tumor located in rectum
5. Have evaluable disease in MRI
6. Have adequate hematological function: hemoglobin >= 9 g/dL, neutrophils >= 1.5 × 109/L and platelets >= 100 × 109/L
7. Have adequate renal function: serum creatinine <= 1.5 × upper limit of normal (ULN) or creatinine clearance >= 50 mL/min
8. Have adequate liver function: aspartate aminotransferase, alanine transaminase, alkaline phosphatase <= 3 × ULN, and bilirubin <= 1.5 × ULN
Sex
9. Are male or female
• Male participants:
Agree to the following during the study intervention period and for at least 12 weeks after the last dose of study intervention:
o Refrain from donating sperm
Plus, either:
o Abstain from any activity that allows for exposure to ejaculate.
OR
o Use a male condom:
- When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with
a failure rate of <1% per year, since a condom may break or leak.
- When engaging in any activity that allows for exposure to ejaculate.
- Female Participants:
o Are not pregnant or breastfeeding, and at least one of the following conditions applies:
- Not a WOCBP
OR
-If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of <1% per year), preferably with low user dependency, as
described for the following time periods:
o Before the first dose of the study intervention(s), if using hormonal contraception:
- Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses
OR
- Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly
sensitive assay.
AND
- A barrier method.
o During the intervention period
o After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 12 weeks, after the last dose of study intervention and agree not to donate eggs
(ova, oocytes) for reproduction during this period.
The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
o Have a negative serum pregnancy test, as required by local regulations, within 4 weeks before the first dose of study intervention. Additional requirements for pregnancy testing during and
after study intervention .
-The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
Informed Consent
10. Can give signed informed consent, which includes compliance with the requirements and restrictions listed in an informed consent form (ICF) and this protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subject
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of any other significant medical disease or psychiatric conditions that might in the assessment of the Investigator preclude safe participation in the study
2. History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study intervention
3. Unstable cardiovascular function within 6 months prior to enrollment (i.e., ischemia, symptomatic angina, congestive heart failure, Class III to IV New York Heart Association uncontrolled conduction abnormalities including a history of long QTc syndrome [QTcF > 480 ms] and/or pacemaker, or myocardial infarction)
4. Hypertension uncontrolled by medication (i.e., systolic blood pressure >= 150 mmHg and diastolic blood pressure >= 90 mmHg)
5. History of other malignant disease within the past 5 years, other than successfully treated basal carcinoma of the skin or carcinoma in situ of the cervix
6. Known human immunodeficiency virus positivity, known active viral hepatitis, current alcohol abuse, or cirrhosis.
7. Ongoing active infection other than human immunodeficiency virus, hepatitis B virus, or hepatitis C virus, or treatment with a live attenuated vaccine within 4 weeks of dosing
Prior/Concomitant Therapy
8. Previous radiation therapy to the pelvis
9. Concurrent use of other anticancer therapy
10. Major surgical intervention within 4 weeks prior to the first dose of study intervention. Biopsy(s) to establish the diagnosis for rectal cancer is permitted. Diverting ostomy is permitted
11. Concomitant or prior use of medications or herbal supplements, known to be strong inhibitors of cytochrome P450 (CYP) 3A and/or CYP2C19, unless use can be discontinued 1 week prior to
receiving the first dose of study intervention. Concomitant or prior use of medications or herbal supplements, known to be strong inducers of CYP3A and/or CYP2C19, unless use can be
discontinued at least 3 weeks prior to receiving study
intervention. Concomitant or prior therapy use of medications or herbal supplements mainly metabolized by CYP3A with a narrow therapeutic index must be stopped at least 1 day prior to
receiving study intervention
12. Concomitant use of H2-blocker or proton pump inhibitors (PPIs) (or unable to stop at least 5 days prior to the first treatment). Note that calcium carbonate is acceptable
13. Treatment with sorivudine or its chemically related analogues, such as brivudine
Prior/Concurrent Clinical Study Experience
14. Participation in any interventional clinical study within 28 days prior to Screening or during participation in this study
Diagnostic Assessments
15. Contraindications to MRI imaging
Other Exclusions
16. Pregnant or nursing (lactating) women
17. Known dihydropyrimidine dehydrogenase deficiency
18. History of severe and unexpected reactions to fluoropyrimidine therapy
19. Hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Secondary Objective: Phase II - <br>To evaluate safety and tolerability of M3814 when administered in combination with capecitabine and RT versus placebo, capecitabine and RT<br>To evaluate the efficacy of M3814 when administered in combination with capecitabine and RT versus placebo, capecitabine and RT<br>To measure QoL<br>To investigate the PK of M3814 using population PK modeling;Main Objective: Phase II - <br>To evaluate the efficacy of M3814 in terms of pCR/cCR when administered in combination with capecitabine and RT versus placebo, capecitabine and RT;Primary end point(s): Phase II - <br>Composite endpoint of pCR/cCR;Timepoint(s) of evaluation of this end point: Phase II - <br>Pathology evaluation of specimen after surgery (pCR) and clinical evaluation 1 to 2 weeks prior to surgery (cCR)
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Phase II -<br>-Occurrence of TEAEs and treatment-related adverse events according to the NCI-CTCAE version 5.0<br>-Occurrence of abnormalities (Grade >= 3) in laboratory test values, markedly abnormal vital sign measurements, and clinically significantly abnormal ECGs<br>- Disease-free Survival<br>-Overall Survival<br>-pCR<br>-cCR<br>-Best Overall Response assessed by the Investigator<br>-Local and/or distant recurrence<br>-Neoadjuvant Rectal Score<br>-Surgical intervention in participants who have not undergone primary surgery due to cCR<br>-R0 resection (no residual tumor)<br>-Patient-reported outcomes / health related QoL as reported using the EORTC QLQ-C30, EORTC-CR29, and EQ-5D-5L<br>-PK profile of M3814 in terms of PK parameter estimates (e.g., AUC0-t, CL/f and Vz/f);Timepoint(s) of evaluation of this end point: Throughout the trial