A study to investigate response to ompenaclid combined with FOLFIRI plus bevacizumab in patients with advanced or metastatic colorectal cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Inspirna Inc., Inspirna Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Sep 2023 → 2 Apr 2025

Decision date (initial)

2023-07-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Inspirna Inc.

External identifiers

EU CT number

2023-503356-27-00

WHO UTN

U1111-1287-0704

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety

To compare the efficacy of ompenaclid versus placebo

Secondary objectives 4

1. To compare additional efficacy parameters of ompenaclid versus placebo
2. To determine the safety of treatment with ompenaclid
3. To assess the pharmacokinetics of ompenaclid
4. To evaluate exploratory biomarkers that may correlate with efficacy outcomes

Conditions and MedDRA coding

Metastatic colorectal cancer that is resistant to the currently approved methods of treatment is recognized as a serious threat to public health worldwide. Research efforts in recent years have become increasingly geared towards discovering and developing new treatment regimens with modes of action distinct from those of established agents and with the ability to target subclasses of colorectal cancer, such as those associated with RAS mutations.

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Advanced disease, defined as cancer that is either metastatic or locally advanced and unresectable and for which additional radiation therapy or other locoregional therapies are not considered feasible.
2. Progression of disease after receiving only 1 prior regimen considered standard of care for CRC in the advanced/metastatic setting, and it must have been an oxaliplatin-containing regimen. Patients who have mismatch repair deficiency/ high microsatellite instability (dMMR/MSI-H) CRC must have also received prior treatment with pembrolizumab or a Food and Drug Administration (FDA) /European Union (EU-)-approved programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitor. Patients may have received prior treatment with bevacizumab or an European Medicines Agency (EMA-)-approved biosimilar. Patients who developed metastatic CRC within 12 months of completion of adjuvant oxaliplatin and 5-FU based therapy are also eligible.
3. Histologic or cytologic evidence of a malignant colorectal tumor of adenocarcinoma or poorly differentiated histology that is laboratory-confirmed to be RAS mutant. Confirmation of RAS mutant status by liquid biopsy is acceptable only if the tumor sample is not available and the liquid biopsy was performed before initiation of the patient’s prior treatment regimen. Patients who convert to RAS mutant status after initially having documented wild-type histology are not eligible.
4. Disease that is measurable by standard imaging techniques by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that disease site subsequent to radiation.
5. At least 18 years old.
6. ECOG performance score ≤1.
7. Adequate baseline organ function, as demonstrated by the following: a. Calculated creatinine clearance >60 mL/min per institutional standard b. Serum albumin ≥2.5 g/dL c. Bilirubin ≤1.5 x institutional upper limit of normal range (ULN) d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN; patients with hepatic metastases may have AST and ALT ≤ 5 x institutional ULN e. Absolute neutrophil count (ANC) ≥1.5x10^9/L f. Hemoglobin ≥8 g/dL and no red blood cell (RBC) transfusions during the prior 14 days g. Platelet count ≥100x10^9/L and no platelet transfusions during the prior 14 days
8. If not taking warfarin (or similar vitamin K inhibitor) the following values are required: international normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 x ULN and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 x ULN. Patients on warfarin (or similar vitamin K inhibitor) may be included if on a stable dose with a therapeutic INR <3.5.
9. Left ventricular ejection fraction (LVEF) ≥ 45% as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scanning.
10. Woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 2 weeks prior to treatment.
11. Men and WOCBP must agree to use acceptable contraceptive methods for the duration of time on the study and continue to use acceptable contraceptive methods for at least 6 months from the last dose of bevacizumab or 2 months after the last dose of ompenaclid, whichever is longer.
12. Provides signed informed consent prior to initiation of any study-specific procedures or treatment.
13. Able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.

Exclusion criteria 24

1. Persistent clinically significant toxicities (Grade ≥2) from previous anticancer therapy. Excluded are Grade 2 chemotherapy-related neuropathy and alopecia which are permitted and Grade 2 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the Investigator, or can be managed with available medical therapies.
2. Received treatment with an investigational systemic anticancer agent within 5 half-lives of the investigational systemic therapy or within 28 days, whichever is shorter prior to Study Drug administration.
3. Has an additional active malignancy that may confound the assessment of the study endpoints. Patients with a past cancer history with substantial potential for recurrence must be discussed with the Medical Monitor before study entry. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia, and melanoma in situ), organ-confined prostate cancer with no evidence of progressive disease.
4. Clinically significant cardiovascular disease: e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension (defined as systolic blood pressure [SBP]>160 or diastolic blood pressure [DBP]>90), or clinically significant arrhythmias not controlled by medication.
5. Known active or suspected brain or leptomeningeal metastases. Central nervous system (CNS) imaging is not required prior to study entry unless there is a clinical suspicion of CNS involvement.
6. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant or breast feeding.
8. Any medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicities.
9. Known dihydropyrimidine dehydrogenase (DPD) deficiency or is on treatment with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine, within 4 weeks prior to the start of FOLFIRI treatment.
10. Requires treatment with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors.
11. Evidence of muscular dystrophies or ongoing muscle pathology.
12. Previously received FOLFIRI or other irinotecan containing treatment regimens.
13. Marked proteinuria (≥ 2 g/24 hours) and/or nephrotic syndrome. Patients with a proteinuria 2+ or greater urine dipstick reading should undergo further assessment, e.g., a 24-hour urine collection.
14. History of acute or subacute intestinal occlusion, unless such an event occurred only around the time of initial diagnosis, or development of metastatic disease, or from chronic inflammatory bowel disease or chronic diarrhea.
15. Severe, non-healing wounds, ulcers, or bone fractures.
16. History of hemodynamically significant pulmonary embolism within 6 months prior to inclusion in the study.
17. History of hemorrhagic diathesis or tendency towards thrombosis that is not optimally managed, with the exception of tumor bleeding before tumor resection surgery.
18. Oxygen-support requirements.
19. QTc >470 msec.
20. Physical abnormality or medical condition that limits swallowing multiple pills or has a history of non-adherence to oral therapies.
21. A gastrointestinal (GI) condition that may significantly alter absorption.
22. Clinically significant ascites (i.e., requiring paracentesis within the preceding 28 days or treatment with pain medication).
23. CRC with histology (or component of histology) consistent with small cell, neuroendocrine, or squamous carcinoma, or lymphoma.
24. Received treatment with chemotherapy, external-beam radiation, or other systemic anticancer therapy within 14 days prior to study therapy administration (42 days for prior nitrosourea or mitomycin-C).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall response rate (ORR)

Secondary endpoints 4

1. Progression-free survival (PFS) (key secondary objective): Overall survival (OS); Duration of response (DoR); Disease control rate (DCR)
2. Adverse events, performance status (Eastern Cooperative Oncology Group [ECOG]), physical examinations, clinical laboratory values, vital signs, electrocardiogram
3. Steady state concentration
4. CKB levels identified in baseline tumor samples

Investigational products

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

Test 1

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Inspirna Inc.

Sponsor organisation

Inspirna Inc.

Address

3002 48th Avenue Ste 350

City

Long Island City

Postcode

11101-3432

Country

United States

Scientific contact point

Organisation

Inspirna Inc.

Contact name

Chief Medical Officer

Public contact point

Organisation

Inspirna Inc.

Contact name

Chief Operating Officer

Third parties 6

Inspirna Inc.

Sponsor organisation

Inspirna Inc.

Address

3002 48th Avenue Ste 350

City

Long Island City

Postcode

11101-3432

Country

United States

Scientific contact point

Organisation

Inspirna Inc.

Contact name

Chief Medical Officer

Public contact point

Organisation

Inspirna Inc.

Contact name

Chief Operating Officer

Third parties 6

Sponsor responsibilities

Article 77 compliance

Inspirna Inc.

Contact point sponsor

Inspirna Inc.

Article 77 implementation

Inspirna Inc.

Locations

3 EU/EEA countries · 26 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

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

Application history

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