Clinical trial NCT06856837: - IKF/AIO-QUINTIS - Evaluating Fruquintinib in Combination With Tislelizumab in Microsatellite Stable / Proficient Mismatch Repair (MSS/pMMR) Metastatic Colorectal Cancer Without Active Liver Metastases
Official title: - IKF/AIO-QUINTIS - A Randomized Phase II Trial Evaluating Fruquintinib in Combination With Tislelizumab in Microsatellite Stable / Proficient Mismatch Repair (MSS/pMMR) Metastatic Colorectal Cancer Without Active Liver Metastases
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Lead sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Sponsor class: OTHER
First posted: 2025-03-04
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants eligible for this trial will be randomized 1:1 into one of the two arms (experimental Arm A and control Arm B) stratified by: I) Previous anti-angiogenic therapy (yes vs. no), II) BRAF/RAS mutation status (wildtype vs. mutation), III) History of liver metastases (never vs. prior but treated)
Primary purpose: TREATMENT

Brief summary: This is a prospective, randomized, open-label, multicenter phase II investigating the therapy of Fruquintinib in combination with Tislelizumab in patients with MSS/pMMR metastatic colorectal cancer without liver metastases.

Detailed description: Participants eligible for this trial will be randomized 1:1 into one of the two arms (Arm A and Arm B) stratified by: I) -Previous anti-angiogenic therapy (yes vs. no), II) BRAF/RAS mutation status (wildtype vs. mutation) or III) History of liver metastases (never vs. prior but treated).

Patients in Arm A (experimental arm) will receive Fruquintinib (orally, 5 mg once a day, at day 1-21 of each 28-day cycle \[Q4W\]) plus Tislelizumab (i.v., 400 mg, at day 1 of each 42-day cycle \[Q6W\]).

Patients in Arm B (control arm) will receive Trifluridine/tipiracil (orally, 35 mg/m2 twice a day, day 1-5 and day 8-12 of each 28-day cycle \[Q4W\]) plus Bevacizumab (i.v., 5 mg/kg, at day 1 of each 14-day cycle \[Q2W\]).

The treatment will be performed until disease progression, unacceptable toxicity, patients' request, or end of protocol-defined treatment time (maximum of 15 months).

All patients will be followed up for a maximum of 18 months after last patient in or until death, withdrawal of consent or loss to follow-up, whatever occurs first.

Eligibility criteria: Inclusion Criteria:

1. Patient\* provide signed informed consent form.
2. Patient is ≥ 18 years at the time of given informed consent.
3. Patient has been diagnosed with histologically or cytologically proven microsatellite stable (MSS)/proficient mismatch repair (pMMR) metastatic adenocarcinoma of the colon or rectum, which is not amenable to potentially curative resection.
4. Known RAS (KRAS or NRAS) and BRAF V600E mutational status. Note: These mutations are mutually exclusive. Therefore, if one of the factors is mutated, it is not required to determine the mutation status of the others, as they are then assumed to be wildtype.
5. Patient without liver metastases (NLM) defined as subjects without active liver metastases at screening as determined on baseline imaging of the liver as performed by CT scan with contrast or MRI. Definitively treated liver metastases (which includes surgical resection, microwave or radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) that were treated at least 3 months prior to enrollment with no evidence of radiologic progression on subsequent imaging are considered to be non-active liver metastases.
6. Patient received at least one line of previous treatment with a fluoropyrimidine, oxaliplatin, irinotecan, VEGF(R) and if indicated EGFR and/or BRAF inhibitors in the advanced setting, or the patient has been intolerable or ineligible to those treatments.
7. Patient has an ECOG performance status ≤ 1.
8. Patient has a life expectancy \> 16 weeks.
9. Patient has adequate hematological, hepatic and renal function.

   1. Absolute number of neutrophils (ANC) ≥ 1.5 x 109/L
   2. Platelets ≥ 100 x 109/L
   3. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (or \< 2 x ULN in case of prior liver involvement or Gilbert's disease)
   4. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN, AP ≤ 5 x ULN
   5. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (measured by 24 h urine) ≥ 30 mL/min (i.e., if serum creatinine level is \> 1.5 x ULN, then a 24-hour urine test must be performed to check the creatinine clearance to be determined).
   6. Urinary protein ≤2+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥3+, a 24-hour urine collection for protein must demonstrate \<2000 mg of protein in 24 hours to allow participation in this protocol)
10. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy).
11. Female patients of childbearing potential or male patients in Arm B with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 6 months after the last trial treatment. Male patients in Arm B with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy. Female patients of child-bearing potential must have a negative pregnancy test within the last 7 days prior to the start of trial therapy.
12. Patient is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

    * There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the trial gender-independently.

Exclusion Criteria:

1. Patient has known allergic / hypersensitive reactions to at least one of the treatment components
2. Patient had previous malignancy other than that under study within 3 years or concomitant malignancy, except: those with a 5-year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer
3. Patient received previous treatment with Fruquintinib, trifluridine/tipiracil, regorafenib or an anti-PD-1/anti-PD-L1 antibodies.
4. Patient receives current treatment with any anti-cancer therapy, such as systemic immunotherapy, chemotherapy, or hormone therapy within ≤ 2 weeks prior to study treatment start.
5. Patient receives simultaneous treatment with a different anti-cancer therapy other than that provided for in the trial (excluding palliative radiotherapy for symptom control).
6. Patient has known untreated or symptomatic CNS or leptomeningeal metastases.
7. Patient has impaired cardiac function or clinically significant cardiac disease including unstable angina within 6 months before the first dose of study treatment, acute myocardial infarction \< 6 months prior to the first dose of study treatment, New York Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled hypertension (defined as an average systolic blood pressure \> 160 mmHg or diastolic \> 100 mmHg despite optimal treatment, uncontrolled cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, active coronary artery disease or corrected QT interval (QTc) ≥ 470.
8. Patient has history of uncontrolled infection with human deficiency virus (HIV) or chronic infection with hepatitis B or C virus (HBV, HCV).
9. Patient has evidence of bleeding diathesis.
10. Patient has history of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation.
11. Patient has grade 3-4 gastrointestinal bleeding within 3 months prior to first dose of trial therapy.
12. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug (see Appendix 4 for examples).
13. Patient had a major surgery within 2 weeks prior to first dose of trial therapy.
14. Patient experienced severe, life-threatening, or recurrent (Grade 2 or higher) immune-mediated adverse events (AEs) or infusion-related reactions including those that led to permanent discontinuation while on treatment with immune-oncology agents.
15. Patient received prior immunosuppressive therapy: immunosuppressive doses of systemic medications of \> 10 mg/day of prednisone or equivalent must be discontinued ≥ 2 weeks before the first dose of study treatment. Short courses of high dose corticosteroids and/or continuous low dose of prednisone (\< 10 mg/day) are permitted. In addition, inhaled, intranasal, intraocular, and/or joint injections of corticosteroids are allowed.
16. Patient has active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study.
17. Patient has history of solid organ transplantation .
18. Patient has history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 months or history of stroke and/or transient ischemic attack within the last 12 months.
19. Patients has evidence of any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
20. Female patient is pregnant or breast feeding or planning to become pregnant within and up to 6 months after end of treatment.

Primary outcomes:
measure: To evaluate the efficacy of Fruquintinib in combination with the PD-1 inhibitor Tislelizumab in MSS/pMMR metastatic colorectal cancer without liver metastases.
timeFrame: up to 54 month
Secondary outcomes:
measure: Overall survival
timeFrame: up to 54 month
measure: Objective response rate
timeFrame: up to 54 month
measure: Disease control rate
timeFrame: up to 54 month
measure: Duration of response
timeFrame: up to 54 month
measure: To evaluate the safety and tolerability of Fruquintinib in combination with the PD-1 inhibitor Tislelizumab in MSS/pMMR metastatic colorectal cancer without liver metastases.
timeFrame: up to 54 month
measure: To assess health-related quality of life (HRQoL) data of Fruquintinib in combination with the PD 1 inhibitor Tislelizumab in MSS/pMMR metastatic colorectal cancer without liver metastases.
timeFrame: up to 54 month
Other outcomes:
measure: Exploratory Translational Objectives
timeFrame: up to 54 month
Locations:
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH
city: Salzburg
country: Austria
facility: SCRI CCCIT Ges.m.b.H.
city: Wiener Neustadt
country: Austria
facility: Noe LGA Gesundheit Thermenregion GmbH
city: Amberg
country: Germany
facility: Klinikum St. Marien Amberg
city: Bad Saarow
country: Germany
facility: HELIOS Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin KöR
city: Bochum
country: Germany
facility: Katholisches Klinikum Bochum gGmbH
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Klinik für Gastroenterologie, Hepatologie und Infektiologie Gastroonkologische Studienzentrale
city: Essen
country: Germany
facility: KEM | Klinik für Internistische Onkologie gGmbH
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt/main
country: Germany
facility: Institut für Klinisch-Onkologische Forschung am Krankenhaus Nordwest
city: Frankfurt
country: Germany
facility: Goethe University Frankfurt
city: Hamburg
country: Germany
facility: Hamburg Hämatologisch-Onkologische Praxis Eppendorf-Facharztzentrum Eppendorf
city: Hamburg
country: Germany
facility: Asklepios Kliniken Hamburg GmbH
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Herne
country: Germany
facility: Marienhospital Herne
city: Karlsruhe
country: Germany
facility: Vincentius-Diakonissen-Kliniken gAG
city: München
country: Germany
facility: Klinikum der Universität München AöR
city: München
country: Germany
facility: München Klinik gGmbH
city: Münster
country: Germany
facility: Münster, Gemeinschaftspraxis für Hämatologie und Onkologie
city: Schweinfurt
country: Germany
facility: Leopoldina Krankenhaus Schweinfurt
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
Study officials:
affiliation: Frankfurter Institut für Klinische Krebsforschung IKF GmbH
name: Salah-Eddin Al-Batran, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: Hämatologisch-Onkologische Praxis Eppendorf University Cancer Center Hamburg
name: Alexander Stein, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: