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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jul 2023 → ongoing

Decision date (initial)

2025-01-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

External identifiers

EU CT number

2024-518980-37-00

EudraCT number

2022-004167-25

ClinicalTrials.gov

NCT05700656

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Safety

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

Secondary objectives 1

1. To characterize the safety and tolerability. To determine pharmacokinetics. To assess anti-tumor activity, as measured by DOR, TTR, PFS and OS

Conditions and MedDRA coding

colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Histological or cytological proof of CRC with at least confirmed peritoneal metastases (presence of additionalextraperitoneal metastases is allowed);
2. 2. 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
3. 3. Age ≥ 18 years;
4. 4. Able and willing to give written informed consent and informed consent form must have been signed before startof the trial;
5. 5. WHO performance status of ≤1;
6. 6. Able and willing to undergo blood sampling for PK analysis;
7. 7. Able and willing to undergo tumor biopsy before start, during treatment and at the end of treatment;
8. 8. Life expectancy > 3 months allowing adequate follow up of toxicity and anti-tumor activity;
9. 9. Evaluable disease according to RECIST 1.1 criteria
10. 10. 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);
11. 11. Negative pregnancy test (urine or serum) for female patients with childbearing poten-tial.
12. 12. Able and willing to swallow tablets.

Exclusion criteria 13

1. 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. 2. Known or suspected complete or partial dihydropyrimidine dehydrogenase deficien-cy (Mutant for DPD*2Agenotype, 1236G>A genotype, 1679T>G genotype and 2846A>T genotype);
3. 3. Symptomatic or untreated leptomeningeal disease;
4. 4. Symptomatic brain metastasis.
5. 5. 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;
6. 6. 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;
7. 7. 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);
8. 8. Woman who are pregnant or breast feeding;
9. 9. 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;
10. 10. Active infection requiring systemic antibiotics or uncontrolled infectious disease;
11. 11. Patients with a known history of hepatitis B or C or known Human Immunodeficiency Virus HIV-1 or HIV-2 typepatients;
12. 12. 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;
13. 13. Known hypersensitivity to one of the study drugs or excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 1

1. - 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Neeltje Steeghs

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Neeltje Steeghs

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications