RASTRIC-trial: investigating the safety and efficacy of a new three drug treatment combination for RAS-mutated metastastic colorectal cancer.

Phase 1

• Conditions: colorectal cancer; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2019-004987-23-NL
• Lead Sponsor: MC Utrecht

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-04-21
• Last Update Posted: 21 March 2022

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 47

Inclusion Criteria

1.Histological or cytological proof of CRC.
2.After failure of a minimum of 2 lines of standard of care regimens. Prior lines of treatment must include: a minimum of 2 lines of prior systemic treatment for metastatic disease, including at least fluoropyrimidine, oxaliplatin and irinotecan based treatment (unless contra-indications for either oxaliplatin and/or irinotecan). Adjuvant treatment completed < 6 months before development of metastatic disease will be counted as 1st line for metastatic disease.
3.Written documentation of a known pathogenic RAS mutation.
4.Age ? 18 years.
5.Able and willing to give written informed consent.
6.Measurable disease according to RECIST 1.1
7.WHO performance status of 0 or 1.
8.Able to swallow and retain orally administered medications and does not have clinically significant gastrointestinal abnormalities that may alter absorption (e.g. malabsorption syndrome, ileostomy or major resection of the stomach or bowel)
9.Able and willing to undergo blood sampling.
10.Able and willing to undergo a tumor biopsy prior to start and after two weeks on therapy. Tumor biopsy should be histological. Cytological biopsies are not accepted.
11.All toxicities related to prior treatment should have resolved to CTCAE grade 1 or less (excluding alopecia)
12.Life expectancy ? 3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
13.Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception, throughout the treatment period, and for 4 months after the last dose of study treatment.
14.Adequate organ functions as defined by table 2.

Table 2 Definitions for adequate baseline organ function
Absolute neutrophil count= 1.5 x 109/L
Hemoglobin= 6.0 mmol/L
Platelets= 100 x 109/L
PT/INR and aPTTwithin normal limits (unless anti-coagulant treatment)
Hepatic:
Total bilirubin = 1.5 x ULN
AST and ALT = 2.5 x ULN
Albumin = 30.0 g/L
Lactate dehydrogenase = 2x ULN
Renal:
Serum creatinine= 1.5 x ULN
Or Calculated creatinine clearance
by Cockcroft-Gault formula:= 50 mL/min

Cardiac:
Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA= 50%

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 subjects for this age range 31
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion Criteria

1.Any treatment with investigational drugs within 30 days or 5 half-lives prior to receiving the first dose of investigational treatment.
2.History of another malignancy. Exceptions: Patients who have been disease-free for at least 3 years after treatment with curative intent, or patients with a history of completely resected non-melanoma skin cancer, in situ carcinoma of the cervix and/or patients with indolent completely resected second malignancies are eligible.
3.Symptomatic or untreated leptomeningeal disease.
4.Symptomatic brain metastases. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 6 weeks) are allowed to enrol. Radiotherapy for brain metastases must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive anti-epileptic drugs or corticosteroids.
5.Patients previously treated with combination treatment of drugs known to interfere with EGFR, HER-2, HER-3, HER-4, or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK, and ERK. Single agent targeted therapies interfering with these pathways are allowed for inclusion in phase I.
Exclusion criteria in phase II: patients previously treated with drugs known to interfere with EGFR, HER-2, HER-3, HER-4, or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK, and ERK, both as single agent or in combination.

6.History of interstitial lung disease or pneumonitis
7.Women who are pregnant or breast feeding.
8.Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms).
9.Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
10.Patients who have undergone any major surgery within the last 3 weeks prior to starting study drug or who would not have fully recovered from previous surgery.
11.Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients.
12.Patients with known, active, hepatitis B (HBV) or C virus (HCV).
13.Patients with retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), or with a history of uveitis, retinal vein occlusion, central serous retinopathy, or retinal detachment.
14.Patients with left ventricular ejection fraction (LVEF) < 50%.
15.History or evidence of cardiovascular risk including any of the following:
•A QT interval corrected for heart rate using the Bazett’s formula (QTcB; Appendix X) ?480 msec;
•History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible.
•History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.
•History of or evidence of current congestive heart failure = Class class II co

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified