| Eligibility |
Inclusion Criteria:
1. Signed and dated informed consent obtained before undergoing any study-specific
procedure
2. Male or female aged =18 years
3. Histologically confirmed diagnosis of adenocarcinoma originating from the colon or
rectum, with known RAS and BRAF mutational status as assessed per standard practice
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 (Note: Subjects with lesions in
a previously irradiated field as the sole site of measurable disease will be permitted
to enroll provided the lesion(s) have demonstrated clear progression and can be
measured accurately)
6. 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. Note: Previous oxaliplatin-based adjuvant treatment is considered as a treatment
line if disease relapse occurred within 6 months from its completion
7. Naïve to any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints
inhibitors) and EP4 receptor antagonists
8. Availability of adequate and sufficient baseline tumor tissue sample (archival or
newly obtained biopsy). Note: an adequate and sufficient sample is defined as formalin
fixed paraffin embedded tumor tissue sample, preferably from the most recent biopsy of
a tumor lesion, collected either at the time of or after the diagnosis of metastatic
disease has been made AND from a site not previously irradiated. If no tumor tissue is
available, a fresh tissue from needle or excisional biopsy or from resection is
required
9. pMMR/MSS defined as CRC with all 4 MMR proteins intact AND 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 (Note: 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
8. Proteinuria = 3.5 g/24 hours
13. Ability and willingness to participate and comply with the requirements of the entire
study
Exclusion Criteria:
Medical Condition/History:
-Cancer and anti-cancer therapy:
1. 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 tumor, 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.
Note 1: Patients must have recovered from all AEs due to previous therapies, to CTCAE
=Grade 1 or to baseline condition. Participants with CTCAE =Grade 2 neuropathy or
alopecia may be eligible.
Note 2: If patients received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
treatment.
Note 3: Patients must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease
6. Uncontrolled tumor-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
-Cardiovascular:
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
-Infections:
14. Confirmed infection with SARS-CoV-2 as documented by molecular testing at
nasopharyngeal swab
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
-General Medical History:
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
-Concomitant Treatments
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 Note: Corticosteroid use for management of immune-related adverse
events, and/or as a premedication for iv contrast allergies/reactions is allowed.
Daily corticosteroid replacement therapy is allowed: permitted therapy are daily
prednisone at doses of 5 to 7.5 mg or equivalent hydrocortisone dose, and steroid
therapy administered by topical, intraocular, intranasal, and/or inhalation routes
31. Regular use of any illicit drugs or recent history (within the last year) of substance
abuse (including alcohol)
-Others:
32. Participation in a study with an investigational drug or medical device within 28 days
before Cycle 1 Day 1 Note: Participants who have entered the follow-up phase of
another investigational study may participate as long as at least 4 weeks have elapsed
since the last dose of the investigational agent
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, 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 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
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