Phase I/II study with galunisertib combined with capecitabine in patients with advanced chemotherapy resistant colorectal cancer with peritoneal metastases

Phase 1/2

Recruiting

• Conditions: colorectal cancer

• Registration Number: 2024-518980-37-00
• Lead Sponsor: Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Brief Summary

With this clinical study, we aim to gain more information about the pharmacological characteristics, safety profile, tolerability and efficacy of galunisertib in combination with capecitabine in patients with PM from CRC

Detailed Description

This is a two-center pharmacological open-label non-randomized proof of principle study consisting of two parts: a phase I study evaluating the RP2D of galunisertib in combination with capecitabine; and a phase II study investigating the anti-tumor activity and safety of galunisertib in combination with capecitabine in advanced colorectal cancer (CRC) with peritoneal metastases (PM).

In phase II of the study a Simon two-stage design will be used. 15 patients will be treated with the galunisertib/capecitabine combination. If at least 2 out of 15 patients respond, an additional cohort of 10 patients will be included to a total of 25 patients. With 6 or more responses, the treatment will be declared to be of sufficient activity and with 5 or less it will be declared of insufficient activity.

The galunisertib dose will be 150 mg twice daily (BID) for the first 14 days of every 4-week cycle, which is the maximum tolerated dose when given as single agent (except of day 1 of cycle 1: single dose of galunisertib 150 mg for PK analysis, from day 2: 150 mg BID).

Capecitabine will be dosed during every 14-day on time of galunisertib at 1000 mg/m2 BID, which is the labelled dose as monotherapy and will in case of toxicities be reduced according to standard care.

Clinical assessments will be performed routinely to monitor safety. Anti-tumor activity will be measured by CT scan according to RECIST 1.1 criteria. Tumor biopsies will be obtained for exploratory objectives.

Study Timeline

• Study First Posted: 2025-01-23
• Last Update Posted: 2025-01-23

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 31

Inclusion Criteria

1. Histological or cytological proof of CRC with at least confirmed peritoneal metastases (presence of additionalextraperitoneal metastases is allowed);

2. Minimal acceptable safety laboratory values a. ANC of ≥1.5 x 109 /L b. Platelet count of ≥100 x 109 /L c. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 3.0 x ULN, or ALAT and ASAT < 5x ULN in patients with liver metastases d. Renal function as defined by serum creatinine ≤ 1.5 x ULN e. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);

3. Negative pregnancy test (urine or serum) for female patients with childbearing poten-tial.

4. Able and willing to swallow tablets.

5. Disease progression or relapse upon treatment for advanced CRC with fluoropyrimidine containingchemotherapy as single agent or in combination with other anti-cancer drugs, with no treatment options at time ofinclusion

6. Age ≥ 18 years;

7. Able and willing to give written informed consent and informed consent form must have been signed before startof the trial;

8. WHO performance status of ≤1;

9. Able and willing to undergo blood sampling for PK analysis;

10. Able and willing to undergo tumor biopsy before start, during treatment and at the end of treatment;

11. Life expectancy > 3 months allowing adequate follow up of toxicity and anti-tumor activity;

12. Evaluable disease according to RECIST 1.1 criteria

Exclusion Criteria

1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigationaltreatment and/or radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigationaltreatment. Palliative radia-tion (1x 8Gy) is allowed; except radiotherapy focused on the liver;

2. Active infection requiring systemic antibiotics or uncontrolled infectious disease;

3. Patients with a known history of hepatitis B or C or known Human Immunodeficiency Virus HIV-1 or HIV-2 typepatients;

4. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnor-mality that may increasethe risk associated with study participation or study drug administration or that may interfere with the interpretationof study results and, in the judgment of the investigator, would make the patient inappropriate for the study;

5. Known hypersensitivity to one of the study drugs or excipients.

6. Known or suspected complete or partial dihydropyrimidine dehydrogenase deficien-cy (Mutant for DPD*2Agenotype, 1236G>A genotype, 1679T>G genotype and 2846A>T genotype);

7. Symptomatic or untreated leptomeningeal disease;

8. Symptomatic brain metastasis.

9. History of cardiac disease, including myocardial infarction within 6 months before first dose of study medication,unstable angina pectoris, New York Heart Associa-tion Class III/IV congestive heart failure, or uncontrolledhypertension, major cardiac abnormalities, a predisposition for developing aneurysms including family history ofaneurysms, Marfan syndrome, bicuspid aortic valve, or evidence of damage to the large vessels of the heart;

10. Treatment with CYP3A4 inducers or inhibitors and/or concomitant treatment with CYP2C9 substrates withnarrow therapeutic window, including but not limited to vit-amin K antagonizing anticoagulants (e.g.acenocoumarol, phenprocoumon and war-farin) and phenytoin is not allowed;

11. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oralgalunisertib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, majorsmall bowel surgery);

12. Woman who are pregnant or breast feeding;

13. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or whowould not have fully recovered from previous surgery;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
The primary aim of phase I of the current study is to determine safety and the RP2D of galunisertib plus capecitabine in patients with chemotherapy resistant CRC with PM. The primary aim of phase 2 is to determine the anti-tumor activity, as measured by ORR of galunisertib in combination with capecitabine in patients with chemotherapy resistant CRC with PM.		The primary aim of phase I of the current study is to determine safety and the RP2D of galunisertib plus capecitabine in patients with chemotherapy resistant CRC with PM. The primary aim of phase 2 is to determine the anti-tumor activity, as measured by ORR of galunisertib in combination with capecitabine in patients with chemotherapy resistant CRC with PM.

Secondary Outcome Measures

Name	Time	Method
- To characterize the safety and tolerability of galunisertib in combination with chemotherapy regimens, as assessed by the incidence and severity of adverse events - To asses anti-tumor activity of galunisertib in combination with chemotherapy, as measured by DOR, TTR, PFS and OS (phase II only) - To determine the pharmacokinetic profile of galunisertib in combination with chemotherapy, as measured by plasma concentrations		- To characterize the safety and tolerability of galunisertib in combination with chemotherapy regimens, as assessed by the incidence and severity of adverse events - To asses anti-tumor activity of galunisertib in combination with chemotherapy, as measured by DOR, TTR, PFS and OS (phase II only) - To determine the pharmacokinetic profile of galunisertib in combination with chemotherapy, as measured by plasma concentrations

Trial Locations

Locations (2)

Amsterdam UMC Stichting; 🇳🇱 Amsterdam, Netherlands

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting; 🇳🇱 Amsterdam, Netherlands

Amsterdam UMC Stichting

🇳🇱Amsterdam, Netherlands

Marc Zuurbier

Site contact

0204444254

medonc-lowergi-elderly@amsterdamumc.nl