Metastatic Colorectal

*Patient must be ≥ 18 years of age.
*Patient must have confirmed unresectable liver confined metastatic colorectal cancer (CRC).
*Patient must not have radiographically or clinically evident extrahepatic disease (including but not limited to radiographically positive periportal lymph nodes).
*Patient must have received previous first-line chemotherapy that meets one of the following three criteria: a) have received at least 6 but no more than 12 cycles of first-line cytotoxic chemotherapy (where ECOG-ACRIN EA2222 Cancer Research Group Version Date: November 27, 2024 14 1 cycle = 14 days) OR b) have received at least 4 but no more than 8 cycles of first-line cytotoxic chemotherapy (where 1 cycle = 21 days) OR c) have developed new colorectal liver metastases (CRLM) within 12 months of completing adjuvant systemic therapy for stage II-III colorectal cancer.

Age ≥18 years. Because no dosing or adverse event data are currently available on the use of CA-4948 (emavusertib) and FOLFOX in combination with bevacizumab in patients < Grade 2 (CPK ≤ 2.5 x ULN)

Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start.

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)–directed therapy shows no evidence of progression.
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible, after discussion with the PI or medical monitor, if the treating physician determines that immediate CNS-specific treatment is not required and is unlikely to be required during the first cycle of therapy.

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better.

Inclusion:
2. Histological or cytological confirmed colorectal adenocarcinoma.
3. Evidence of Stage IV metastatic disease.
4. Known RAS mutation status per local test (includes KRAS and NRAS exons 2,3 and 4 codons 12, 13, 59, 61, 117 and 146). Participants with unknown RAS status despite attempt to test are eligible for participation.
5. No prior systemic therapy for metastatic disease.
Note: Participants with early-stage disease who received prior systemic neoadjuvant or adjuvant chemotherapy and present with reoccurrence/metastatic disease within 6 months of stopping treatment will count as having prior therapy in the metastatic setting and are not eligible.


Exclusion:
1. Locally confirmed BRAF V600E mutation
2. Locally confirmed MSI-high or dMMR colorectal cancer
3. Participants with known active symptomatic CNS lesions, including leptomeningeal metastasis, brainstem, meningeal, or spinal cord metastases or compression Note: Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be enrolled if all of the following are met:
a. CNS metastases have been clinically stable with no evidence of clinical or radiographic disease progression for ≥14 days after completion of definitive radiotherapy and/or surgery and prior to study intervention.
b. The participant has not required steroids for brain metastasis symptom management for 7 days prior to first dose of study intervention.
4. Known DPD deficiency (refer to the local 5-FU label or local clinical guidance for DPD status recommendation prior to starting treatment)

* Have histologically or cytologically confirmed adenocarcinoma of the colon or rectum.

* Participants must have recurrent, unresectable or metastatic disease.
Note:
 Carcinoma of the anal canal is excluded.

* Be diagnosed to have KRAS, NRAS, and BRAF WT tumor as determined by local testing.
Both tissue- and blood-based testing is an acceptable method for the eligibility
determination.
The local test must at least include and participants must be WT for KRAS/NRAS G12 and
G13 and BRAF V600 codons. Other KRAS/NRAS codons, as well as MSI-H/dMMR status
and ERBB2/HER2 amplification status, should be determined per the local guidelines and
standard practice. A participant is excluded from the study if the participant is known to
have a mutation (with the exception of a silent mutation) in any of the following codons
based on local testing: KRAS/NRAS G12, G13, A59, Q61, K117, or A146 or BRAF V600.

A copy of the test report documenting the WT status for KRAS/NRAS and BRAF must be
included in the participant records, and a de-identified copy must be submitted to the
sponsor during the screening period.

The local test must be performed prior to randomization in accordance with local
guidelines using an FDA-approved test or laboratory-developed test that is validated in a
CLIA-certified laboratory (sites in the United States) or an accredited local laboratory
(sites outside of the United States). In the European Union, the local test must be
CE-marked or an in-house laboratory-developed test from health institutions in the
European Union in accordance with Article 5(5) of the IVDR 2071/746, as amended.

* Must agree to the submission of fresh or archival tumor tissue post-progression from the
most recent therapy, if clinically feasible.

Prior Therapy Restrictions or Requirements
* Participant must have received 1 line of systemic therapy for mCRC, with documented
radiographic disease progression on or after this line of therapy. The regimen must be
fluoropyrimidine-based and oxaliplatin-based therapy. Prior anti-VEGF therapy is
allowed according to local regulatory approvals and SoC guidelines.
Note:
 Definition of 1 line of therapy equates to disease progression from 1 and only 1 prior
regimen for mCRC.
 Rechallenge of a same regimen after disease progression or maintenance therapy will
not count as an additional line of therapy.
 Recurrence from prior neoadjuvant/adjuvant chemotherapy <12 months from the last
course of systemic chemotherapy is considered as 1 prior line in the metastatic setting
and, with this 1 line, the participant will be eligible for the study

Key eligibility criteria:

Inclusion criteria:
2. Male or female aged ≥18 years.
3. Presence of histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS status for each participant must be documented.
4. Have been previously treated with standard approved therapies:
– Fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy,
– An anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab [regorafenib is NOT an anti-VEGF biologic]),
– If RAS wild-type and medically appropriate, an anti-EGFR therapy (eg, cetuximab, panitumumab), and
– If known MSI-H or dMMR tumor and medically appropriate, a programmed cell death protein 1 (PD1) inhibitor.
5. Self-identify as Black and/or African American or Hispanic and/or Latino or as both.
6. Body weight ≥40 kg.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at screening (Table 16.a, Section 16.1).
8. Have assessable disease according to RECIST version 1.1 (Section 16.2), assessed locally.


Exclusion criteria:
Individuals who meet any of the following criteria will be excluded from participation in this trial:
1.Absolute neutrophil count (ANC) 1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin 2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
2. Serum total bilirubin >1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin
3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
4. Creatinine clearance <30ml/min Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation (see Section 8.3.4.2). Where available and appropriate, other formulae may be used to estimate clearance after consultation with the trial medical monitor.
5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24 hours. Participants with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
6. Uncontrolled hypertension, defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg despite optimal medical management. The participant must have BP below both limits. Repeated assessments are permitted.
7. International normalized ratio (INR) >1.5 × ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the participant is currently receiving or intended to receive anticoagulants for prophylactic purposes.
8. History of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas, or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation within the 6 months prior to screening.
9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening.
10. History of a thromboembolic event, including deep vein thrombosis, pulmonary embolism, or arterial embolism within 6 months prior to screening.
11. Stroke and/or transient ischemic attack within 12 months prior to screening.
12. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction 480 milliseconds or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrom

Key eligibility criteria:

Inclusion criteria:
2. Male or female aged ≥18 years.
3. Presence of histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS status for each participant must be documented.
4. Have been previously treated with standard approved therapies:
– Fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy,
– An anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab [regorafenib is NOT an anti-VEGF biologic]),
– If RAS wild-type and medically appropriate, an anti-EGFR therapy (eg, cetuximab, panitumumab), and
– If known MSI-H or dMMR tumor and medically appropriate, a programmed cell death protein 1 (PD1) inhibitor.
5. Self-identify as Black and/or African American or Hispanic and/or Latino or as both.
6. Body weight ≥40 kg.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at screening (Table 16.a, Section 16.1).
8. Have assessable disease according to RECIST version 1.1 (Section 16.2), assessed locally.


Exclusion criteria:
Individuals who meet any of the following criteria will be excluded from participation in this trial:
1.Absolute neutrophil count (ANC) 1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin 2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
2. Serum total bilirubin >1.5 × the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin
3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases.
4. Creatinine clearance <30ml/min Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation (see Section 8.3.4.2). Where available and appropriate, other formulae may be used to estimate clearance after consultation with the trial medical monitor.
5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24 hours. Participants with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
6. Uncontrolled hypertension, defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg despite optimal medical management. The participant must have BP below both limits. Repeated assessments are permitted.
7. International normalized ratio (INR) >1.5 × ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the participant is currently receiving or intended to receive anticoagulants for prophylactic purposes.
8. History of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas, or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation within the 6 months prior to screening.
9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening.
10. History of a thromboembolic event, including deep vein thrombosis, pulmonary embolism, or arterial embolism within 6 months prior to screening.
11. Stroke and/or transient ischemic attack within 12 months prior to screening.
12. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction 480 milliseconds or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrom

Cohort B5 is for ATM negative CRC (tested centrally) for 3rd line use with irinotecan plus IP; they don’t count targeted therapies as a line of therapy so anticipate people would have had 5fu, oxaliplatin and irinotecan already, so can add to the metastatic colorectal cancer flowsheet with the 3rd line and above studies

Cohort B6 is for ATM low pancreas adenocarcinoma and would highlight this also includes acinar cell carcinomas, max of 1 prior line of therapy combined with irinotecan, so can put on the Refractory column of the Pancreas flowsheet