High-risk Microsatellite-stable Colorectal Cancer

Primary Objective: To compare the efficacy of mFOLFOX6 plus novel oncology therapy combinations versus mFOLFOX6 alone at 6 months Secondary Objective: 1. To evaluate the safety and tolerability profile of mFOLFOX6 plus novel oncology therapy combinations 2. To compare the efficacy of mFOLFOX6 plus novel oncology therapy combinations versus mFOLFOX6 alone 3. To describe the PK of novel agents when used in combination with mFOLFOX6 4. To assess the immunogenicity of novel biologic agents when used in combination with mFOLFOX6

durvalumab, oleclumab, monalizumab

durvalumab, oleclumab, monalizumab

vial
vial
vial

500 mg
500 mg
375 mg

Primary Endpoint:
ctDNA clearance, defined as the ctDNA
status change from ctDNA positive at
baseline to ctDNA negative postrandomization

Secondary Endpoints:
1. Incidence of AEs, SAEs, laboratory
findings, and vital signs
2. DFS, DFS-12, and OS
3. PK (drug concentration) for novel agents
in combination therapies
4. Incidence of ADA to novel biologic agents
in combination therapies

1 Written informed consent and any locally required authorization (eg, Health Insurance
Portability and Accountability Act in the United States of America [USA]) obtained from
the subject/legal representative prior to performing any protocol-related procedures,
including screening evaluations.
Age
2 Age ≥ 18 years at the time of screening
Type of Subject and Disease Characteristics
3 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4 Histologically proven high-risk Stage II or Stage III CRC per AJCC staging manual
(Amin et al, 2017). Subjects must also meet the following criteria:
(a) Stage II high risk: Any T4 lesion OR a T3 lesion with any one of the following
characteristics: high grade (3), clinical presentation with bowel obstruction and
perforation, histological signs of vascular, lymphatic and perineural invasion,
≤ 12 lymph nodes examined.
(b) Eligible for 6 months of mFOLFOX6 adjuvant chemotherapy within 8 weeks after
surgery.
(c) Must NOT have received prior systemic chemotherapy, immunotherapy, or
radiotherapy for treatment of CRC.
(d) Must NOT have defective DNA mismatch repair (MSI) as documented by testing.
Testing may be performed locally, and prior documentation of this testing is
acceptable in lieu of repeating the test. Defective DNA mismatch repair is defined by
either:
(i) High-frequency MSI with changes detected in 2 or more panels of microsatellite
markers (BAT-25, BAT-26, NR-21, NR-24, or MONO-27), or
(ii) Immunohistochemical analysis demonstrating absence of protein expression of
any one or more of the following proteins: MLH1, MSH2, MSH6, or PMS2.
5 Margin-negative (R0; defined as > 1 mm clearance) surgical resection.
6 Postoperative ctDNA-positive status defined by the presence of ctDNA derived from
plasma; determined using a validated assay based on next generation sequencing of
primary tissue and plasma-derived DNA (see Section 4.3.1.5) and performed in a testing
laboratory approved by the sponsor. Note: Subjects with test results for ctDNA that are
unknown or inconclusive are ineligible for enrollment.
Laboratory Parameters
7 Subjects must have adequate organ function, as determined by:
(a) Hematological (cannot be met with blood transfusions or growth factor support
within 2 weeks of scheduled first dose of study treatment)
(i) Absolute neutrophil count ≥ 1.5 × 109
/L
(ii) Platelet count ≥ 100 × 109
/L
(iii) Hemoglobin ≥ 9.0 g/dL
(b) Renal
(i) Calculated creatinine clearance by Modification of Diet in Renal Disease
equation (Levey et al, 2006) or 24hour urine creatinine clearance > 40 mL/min
(c) Hepatic
(i) Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) (or ≤ 3 ULN in the
presence of documented Gilbert’s syndrome)
(ii) Alanine aminotransferase (ALT) and AST ≤ 2.5 × ULN
Weight
8 Body weight > 35 kg
Lifestyle/Reproduction
9 Females of childbearing potential who are sexually active with a nonsterilized male
partner must use at least one highly effective method of contraception (see Appendix A
for definition of females of childbearing potential and for a description of highly effective
methods of contraception) from screening through 180 days after receipt of the final dose
of investigational product. It is strongly recommended for the male partner of a female
subject to also use male condom plus spermicide throughout this period. Cessation of
contraception after this point should be discussed with a responsible physician. Periodic
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of
contraception. In addition, female subjects must refrain from egg cell donation and
breastfeeding while on study and for 180 days after the final dose of investigational
product.
10 Nonsterilized male subjects who are sexually active with a female partner of childbearing
potential must use a male condom with spermicide from screening through 180 days after
receipt of the final dose of investigational product. It is strongly recommended for the
female partner of a male subject to also use a highly effective method of contraception
throughout this period, as described in Appendix A. In addition, male subjects must
refrain from sperm donation while on study and for 180 days after the final dose of
investigational product.

Medical Conditions
1 Any condition that, in the opinion of the investigator, would interfere with evaluation of
the investigational product or interpretation of subject safety or study results.
2 Evidence of metastatic disease (including presence of tumor cells in ascites or peritoneal
carcinomatosis resected “en bloc”).
3 History of allogeneic organ transplantation.
4 Active or prior documented autoimmune disorders within the past 5 years prior to the
scheduled first dose of study treatment. The following are exceptions to this criterion:
(a) Subjects with vitiligo or alopecia.
(b) Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Subjects with celiac disease controlled by diet alone.
5 Cardiac and vascular criteria:
(a) History of venous thrombosis within the past 3 months prior to the scheduled first
dose of study treatment.
(b) Presence of acute coronary syndrome including myocardial infarction or unstable
angina pectoris, other arterial thrombotic event including cerebrovascular accident or
transient ischemic attack or stroke within the past 6 months prior to the scheduled
first dose of study treatment.
(c) New York Heart Association Class II or greater congestive heart failure, serious
cardiac arrhythmia requiring medication, or uncontrolled hypertension (≥ 160 mmHg
systolic and/or ≥ 100 mmHg diastolic, despite appropriate antihypertensive
medication).
(d) History of hypertensive crisis/hypertensive encephalopathy within the past 6 months
prior to the scheduled first dose of study treatment.
(e) Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
calculated from 3 electrocardiograms (ECGs; within 5 minutes at 1 minute apart,
manually read).
6 Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection,
interstitial lung disease, neuropathy ≥ Grade 2, serious chronic gastrointestinal conditions
associated with diarrhea, or psychiatric illness/social situations that would limit
compliance with study requirements, substantially increase risk of incurring AEs or
compromise the ability of the subject to give written informed consent.
7 History of another primary malignancy except for:
(a) Malignancy treated with curative intent and with no known active disease ≥ 5 years
prior to the scheduled first dose of study treatment and of low potential risk for
recurrence.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
(c) Adequately treated carcinoma in situ without evidence of disease.
8 History of active primary immunodeficiency.
9 Active infection including tuberculosis (clinical evaluation that includes clinical history,
physical examination and radiographic findings, and tuberculosis testing in line with local
practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C,
or human immunodeficiency virus (positive HIV 1/2 antibodies). NOTE:
(a) Subjects with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects
with chronic hepatitis B, confirmed by the presence of anti-HBc, receiving antiviral
therapy may be enrolled if the disease is controlled for at least 1 month prior to
screening. Controlled hepatitis B is defined as serum HBV DNA < 2,000 IU/mL by
polymerase chain reaction (PCR). Subjects with controlled hepatitis B must remain
on antiviral therapy, per institutional practice, to ensure adequate viral suppression,
during the study.
(b) Subjects positive for hepatitis C virus (HCV) antibody are eligible only if PCR is
negative for HCV RNA.
(c) Subjects positive for HIV are eligible only if all criteria below are met:
(i) No history of acquired immunodeficiency syndrome (AIDS)-defining conditions
(ii) Not currently receiving prophylactic therapy for an opportunistic infection and
must not have had an opportunistic infection within the previous 6 months
(iii) On a stable regimen of highly active antiretroviral therapy (HAART) for the past
3 months and will remain on the same regimen during the study
(iv) Current HAART regimen has a low potential for drug-drug interaction or
overlapping toxicity with the study drugs
(v) HIV viral load consistently below the detectable limit for the past 3 months
(vi) CD4 count consistently ≥ 350 cells/mm3
for the past 3 months
10 Known allergy or hypersensitivity to any of the investigational product or
non-investigational product formulations.
11 Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or
inability to take oral medication.
12 Known dihydropyrimidine dehydrogenase (DPD) deficiency. Testing for DPD deficiency
must be performed where required by local regulations, using a validated method that is
approved by local health authorities.
13 Any condition that, in the opinion of the investigator, would prevent the initiation of
6 months adjuvant therapy within 8 weeks of surgery including, but not limited to,
≥ Grade 2 wound dehiscence or ≥ Grade 2 wound complication.
Prior/Concomitant Therapy
14 Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for
cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(eg, hormone replacement therapy) is acceptable.
15 Receipt of live attenuated vaccine within 30 days prior to the scheduled first dose of study
treatment.
16 Major surgical procedure, open biopsy, or significant traumatic injury (all as defined by
the investigator) within 28 days prior to the scheduled first dose of study treatment, or
anticipation of the need for major surgical procedure during the course of the study.
17 Current or prior use of immunosuppressive medication within 14 days prior to the
scheduled first dose of study treatment. The following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular
injection).
(b) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication
or chemotherapy premedication per institutional practice).
Prior/Concurrent Clinical Study Experience
18 Participation in another clinical study with an investigational product administered within
28 days prior to the scheduled first dose of study treatment.
19 Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an interventional
study.
Other Exclusions
20 Female subjects who are pregnant, breastfeeding, or intend to become pregnant during
their participation in the study.
21 Involvement in the planning and/or conduct of the study (applies to both sponsor staff
and/or staff at the study site).
Genetic Research Study (Optional):
22 Exclusion criteria for participation in the optional (DNA) genetics research component of
the study include:
(a) Non-leukocyte-depleted whole blood transfusion within 120 days of genetic sample
collection.