A study to evaluate the safety and efficacy of CR6086 in combination with balstilimab (AGEN2034), in patients with pretreated mismatch-repair-proficient and microsatellite stable metastatic colorectal cancer, and other metastatic GI cancers

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rottapharm Biotech S.r.l.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Nov 2021 → ongoing

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Rottapharm Biotech S.r.l

External identifiers

EU CT number

2024-515446-16-00

EudraCT number

2020-002435-29

ClinicalTrials.gov

NCT05205330

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

Main Study – patients with MSS mCRC
Primary objective
 To evaluate the therapeutic potential of vorbipiprant (CR6086) in combination with ICIs (here represented by the PD-1 inhibitor AGEN2034) in the treatment of pMMR–MSS metastatic CRC, assessed when all patients at the highest Dose Level tested have completed 24 weeks of treatment, unless they discontinued earlier, based on:
1. The safety and tolerability of the combination in the target population
2. The preliminary efficacy of the combination in the target population, as determined by:
 the Disease Control Rate (DCR) during the Dose Escalation part
 the Objective Response Rate (ORR) during the Expansion part (Phase IIa)
 To select the best performing dose of CR6086 to be recommended for future combination studies in immuno-oncology indications, according to the parameters above.

Study Extension – patients with other metastatic GI cancers
Primary objective
 To evaluate the therapeutic potential of vorbipiprant (CR6086) in combination with ICIs (here represented by the PD-1 inhibitor AGEN2034) in the treatment of metastatic GI cancers, assessed when patients have completed 24 weeks of treatment, unless they discontinued earlier, based on:
1. The safety and tolerability of the combination in the target population
2. The preliminary efficacy of the combination in the target population as determined by the Disease Control Rate (DCR)

Secondary objectives 2

1. Main Study – patients with MSS mCRC: Secondary objectives  To further assess the preliminary anti-tumour activity of the combination in terms of Disease Control Rate (DCR) or Objective Response Rate (ORR) as applicable, Duration Of Response (DOR), Progression-Free Survival (PFS), Progression-Free Survival Rate (PFSR) and Overall Survival (OS), in the target population throughout the study.  To investigate the sustained safety and tolerability of the combination throughout the study.
2. Study Extension – patients with other metastatic GI cancers: Secondary objectives  To further assess the preliminary anti-tumour activity of the combination in terms of Objective Response Rate (ORR), Duration Of Response (DOR), Progression-Free Survival (PFS), Progression-Free Survival Rate (PFSR) and Overall Survival (OS), in the target population throughout the study.  To investigate the sustained safety and tolerability of the combination throughout the study.

Conditions and MedDRA coding

Pretreated mismatch-repair-proficient and microsatellite stable metastatic colorectal cancer, and other metastatic GI cancers

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 40

1. Main Study: Signed and dated informed consent obtained before undergoing any study-specific procedure
2. Male or female aged ≥18 years
3. ESC - Histologically confirmed diagnosis of adenocarcinoma originating from the colon or rectum, with known RAS and BRAF mutational status as assessed per standard practice. EXP - Histologically confirmed diagnosis of adenocarcinoma originating from the colon or rectum, with known RAS and BRAF mutational status as assessed per standard practice. For patients included in the Expansion part only: PD-L1 CPS or adequate tissue to perform PD-L1 CPS assessment should be available.
4. Stage IV (according to the American Joint Committee on Cancer definition)
5. Presence of measurable disease per RECIST v1.1 (based on imaging within 28 days from first study drug administration). Patients must have at least one "target lesion" to be used to assess response, as defined by RECIST v1.1
6. ESC - Disease progression after at least two standard treatment lines for mCRC, including fluoropyrimidines, oxaliplatin and irinotecan and, if RAS and BRAF wild-type, cetuximab or panitumumab or, intolerance or refusal of chemotherapy regimens for mCRC
7. Naïve to any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints inhibitors) and EP4 receptor antagonists
8. ESC - Availability of adequate and sufficient baseline tumour tissue sample (archival or newly obtained biopsy) EXP - Availability of adequate and sufficient newly obtained fresh tumour tissue sample collected after ICF during the screening period and before the treatment starts. In case the biopsy collection is not feasible, according to Investigator judgement or patient decision, archival biopsy or surgical sample can be accepted after discussion with the Sponsor.
9. pMMR/MSS defined as CRC with all 4 MMR proteins intact and/or with instability at ≤1/5 locus (or 30% of loci if larger panel of markers are assayed)
10. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
11. Anticipated life expectancy ≥ 3 months
12. Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: 1. Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 2. Creatinine clearance ≥ 50 mL/min 3. Amylase and lipase ≤ 1.5 × ULN 4. Serum bilirubin ≤ 1.5× ULN 5. AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: - Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 6. INR and PTT ≤ 1.5 × ULN. - Patients who are on therapeutic doses of anti-coagulants should be on a stable dose for 28 days, with stable INR and PTT values. 7. Serum albumin ≥ 3.0 g/dL
13. Ability e and willingness to participate and comply with the requirements of the entire study
14. Study Extension_Cohort A and B: Signed and dated informed consent obtained before undergoing any study-specific procedure
15. Study Extension_Cohort A and B: Male or female aged ≥18 years
16. Body weight > 40kg
17. Histologically proven advanced-stage unresectable adenocarcinoma of the stomach or the GEJ
18. Stage IV (according to the American Joint Committee on Cancer definition)
19. Available CPS or available tissue to perform CPS assessment: Cohort A: CPS≥5 - Cohort B CPS<5
20. Failure to at least one prior line of chemotherapy for metastatic disease, given with or without trastuzumab, with or without anti-PD-1. In alternative, early disease recurrence after surgery with neo-adjuvant and/or adjuvant chemotherapy (within 6 months of the last administration of chemotherapy) or progression during neo-adjuvant and/or adjuvant chemotherapy (containing fluoropyrimidine and a platinum derivative).
21. Presence of measurable disease per RECIST v1.1 (based on imaging within 28 days from first study drug administration). Patients must have at least one "target lesion" to be used to assess response, as defined by RECIST v1.1
22. Naïve to EP4 receptor antagonists
23. Availability of adequate and sufficient baseline tumour tissue sample (archival or newly obtained biopsy)
24. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
25. Anticipated life expectancy ≥ 3 months
26. Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: 1. Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 2. Creatinine clearance ≥ 50 mL/min 3. Amylase and lipase ≤ 1.5 × ULN 4. Serum bilirubin ≤ 1.5× ULN 5. AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: - Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 6. INR and PTT ≤ 1.5 × ULN. - Patients who are on therapeutic doses of anti-coagulants should be on a stable dose for 28 days, with stable INR and PTT values. 7. Serum albumin ≥ 3.0 g/dL
27. Ability e and willingness to participate and comply with the requirements of the entire study
28. Study Extension_Cohort C: Signed and dated informed consent obtained before undergoing any study-specific procedure
29. Male or female aged ≥18 years
30. Body weight > 40kg
31. Histologically proven advanced-stage unresectable GI cancer other than CRC and GC
32. Stage IV (according to the American Joint Committee on Cancer definition)
33. Failure to at least one prior line of chemotherapy for metastatic disease, given with or without trastuzumab, with or without anti-PD-1. In alternative, early disease recurrence after surgery with neo-adjuvant and/or adjuvant chemotherapy (within 6 months of the last administration of chemotherapy) or progression during neo-adjuvant and/or adjuvant chemotherapy (containing fluoropyrimidine and a platinum derivative).
34. Presence of measurable disease per RECIST v1.1 (based on imaging within 28 days from first study drug administration). Patients must have at least one "target lesion" to be used to assess response, as defined by RECIST v1.1
35. Naïve to EP4 receptor antagonists
36. Availability of adequate and sufficient baseline tumour tissue sample (archival or newly obtained biopsy)
37. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
38. Anticipated life expectancy ≥ 3 months
39. Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: 1. Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 2. Creatinine clearance ≥ 50 mL/min 3. Amylase and lipase ≤ 1.5 × ULN 4. Serum bilirubin ≤ 1.5× ULN 5. AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: - Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 6. INR and PTT ≤ 1.5 × ULN. - Patients who are on therapeutic doses of anti-coagulants should be on a stable dose for 28 days, with stable INR and PTT values. 7. Serum albumin ≥ 3.0 g/dL
40. Ability e and willingness to participate and comply with the requirements of the entire study

Exclusion criteria 40

1. Main and Extension Study: Additional malignancy that progressed or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin that has undergone potentially curative therapy with no evidence of recurrence for 5 years since initiation of that curative therapy, or carcinoma in situ (breast carcinoma, cervical cancer)
2. Active brain tumour, metastasis or leptomeningeal metastases. Patients with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI except where contraindicated in which CT scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. Cases should be discussed with the Sponsor. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (>10mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
3. Major surgery within 28 days before Cycle 1 Day 1 or anticipation of needing such procedure during the trial
4. Treatment with any systemic or localized anti-cancer therapy, including chemotherapy, biological therapy, radiotherapy, or hormonal therapy within 28 days before initiation of Cycle 1 Day 1 or expected to required such a treatment during the trial
5. Persistent toxicity related to prior therapy, Grade >1 according to NCI CTCAE Version 5.0
6. Uncontrolled tumour-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry
7. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters are allowed
8. Unstable angina
9. Myocardial infarction within 6 months before enrolment
10. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months before enrolment
11. Uncontrolled ventricular arrhythmia
12. Congestive heart failure (New York Hearth Association class ≥II)
13. Poorly controlled hypertension
14. Confirmed infection with SARS-CoV-2 as documented by molecular testing at nasopharyngeal swab (only if required by the epidemiological situation)
15. HIV infection
16. Active tuberculosis
17. Acute or chronic viral hepatitis B or C infection
18. Any severe infection within 14 days before Cycle 1 Day 1
19. Active autoimmune disease in the past 2 years
20. History of allogenic tissue/solid organ transplant (including allogeneic bone marrow transplantation)
21. History of immunodeficiency
22. History or presence of interstitial lung disease or history of pneumonitis that has required oral or iv corticosteroids.
23. History of gastric/duodenal ulcers, colitis and/or gastrointestinal bleeding
24. History of severe gastrointestinal adverse reactions
25. History of hypersensitivity reactions to fully human monoclonal antibodies, Grade ≥ 3 according to NCI CTCAE Version 5.0
26. History of anaphylaxis, or uncontrolled asthma
27. Allergy/hypersensitivity/intolerance to any component of CR6086 or AGEN2034
28. Any other clinically relevant disease and condition, including psychiatric or substance abuse disorders, that, in the opinion of the Investigator, may jeopardize efficacy or safety assessments, confound the result of the trial or may compromise the patient’s safety during trial participation
29. Administration of a live, attenuated vaccine within 28 days before Cycle 1 D1
30. Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before screening
31. Regular use of any illicit drugs or recent history (within the last year) of substance abuse (including alcohol)
32. Participation in a study with an investigational drug or medical device within 28 days before Cycle 1 Day 1
33. Inability to swallow medications
34. Malabsorption conditions
35. For women of childbearing potential:  Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding  Failure to agree to practice a highly effective method of contraception (see Section 12.4), from enrolment up to at least 120 days after the last IMP intake  expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment
36. For sexually active men with a female partner of childbearing potential: failure to agree to use condom (see Section 12.4) and refrain from donating sperm from enrolment up to at least 120 days after the last IMP intake
37. Patients who are legally incapacitated or has limited legal capacity
38. Study Extension only: Presence of portal hypertension
39. Presence of oesophageal varices
40. Presence of gastric infiltration, severe gastritis, duodenal or gastric ulcer, or any other condition that may lead to bleeding or perforation, as assessed by an EGDS performed during screening period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Safety and tolerability: Incidence of DLTs (Main Study/Dose Escalation only only)
2. Safety and tolerability: Incidence of Treatment Emergent Adverse Events (TEAEs) occurring while patients are on treatment or up to 30 days after the last dose of last study treatment
3. Safety and tolerability: Incidence of Serious Adverse Events (SAEs) occurring while patients are on treatment or up to 90 days after the last dose of last study treatment or to a minimum of 30 days after the last IMP intake in case of initiation of new anti-cancer therapy, whichever occurs first
4. Safety and tolerability: Changes in clinical laboratory parameters, vital signs, ECOG performance status, ECG and physical examination
5. Efficacy: DCR, defined as the proportion of patients who have achieved CR, PR, or stable disease (SD)
6. Efficacy: ORR, defined as the proportion of patients who have achieved CR or PR

Secondary endpoints 7

1. Exploratory: PD-L1 expression by CPS (Main Study/Expansion)
2. Exploratory: Change in biomarkers in blood and tumour samples
3. Exploratory: Change in blood and tumour-infiltrating immune cells
4. Efficacy: DOR, defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression
5. Efficacy: PFS, defined as the time from the first dose of study drugs to the earlier date of assessment of progression, or death by any cause in the absence of progression
6. Efficacy: PFSR, defined as the proportion of patients alive and free of disease progression at specific timepoints
7. Efficacy: OS, defined as the time from the first dose of study drugs to the date of death by any cause

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rottapharm Biotech S.r.l.

Sponsor organisation

Rottapharm Biotech S.r.l.

Address

Via Valosa Di Sopra 9

City

Monza

Postcode

20900

Country

Italy

Scientific contact point

Organisation

Rottapharm Biotech S.r.l.

Contact name

Nadia Brambilla

Public contact point

Organisation

Rottapharm Biotech S.r.l.

Contact name

Nadia Brambilla

Third parties 1

Locations

1 EU/EEA country · 3 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 9 files

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

Application history

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