PhII Trial Panitumumab, Nivolumab, Ipilimumab in Kras/Nras/BRAF Wild-type MSS Refractory mCRC

The investigators will conduct a single-arm, open-label Phase II clinical trial investigating
the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable,
refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal
cancer (mCRC). There will be an initial safety lead-in cohort to ensure the combination is
well-tolerated. The primary objective of this study is to estimate the overall response rate
in these subjects at 12 weeks . Secondary objectives include the following: estimating the
overall response rate in these subjects at 12 weeks by immune-related RECIST criteria
(irRECIST), estimating the best response rate by both RECIST 1.1 and irRECIST criteria,
estimating progression-free survival (PFS) and duration of response using both RECIST 1.1 and
irRECIST criteria, estimating overall survival (OS), and characterizing the safety issues
associated with this regimen. Exploratory objectives involve investigating various biomarkers
and peripheral blood and tumor assays.

Inclusion Criteria:

1. Histologically or cytologically confirmed colorectal adenocarcinoma, with unresectable
metastatic or locally advanced disease documented on diagnostic imaging studies.

2. Previously received 1-2 prior lines of therapy. Subjects who relapse within 6 months
of adjuvant chemotherapy comprised of oxaliplatin and a fluoropyrimidine will have
their adjuvant therapy count as one prior line of therapy.

3. Confirmed wild-type in KRAS and NRAS codons 12, 13, 59, 61, 117, and 146; and BRAF
codon 600, by standard of care testing of tumor specimen. Tissue used for testing may
have been collected from primary or metastatic site.

4. Microsatellite stable as detected by PCR-based assay or CLIA-certified sequencing
methodology such as Foundation One; or mismatch repair proficient as detected by
immunohistochemistry showing intact nuclear staining of MLH1, MSH2, MSH6, and PMS2

5. Radiographically measurable disease present per RECIST 1.1

6. Age ≥ 18 years at the time of consent.

7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

8. Blood counts performed within 3 weeks prior to starting study therapy must have
absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and hemoglobin ≥ 9
g/dL.

*Note: Hematology and other lab parameters that are ≤ grade 2 but still meet criteria
for study entry are allowed. Furthermore, changes in laboratory parameters during the
study should not be considered adverse events unless they meet criteria for dose
modification(s) of study medication outlined by the protocol and/or worsen from
baseline during therapy.

9. Liver function tests performed within 3 weeks prior to starting study therapy must
have total bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase and
aspartate aminotransferase ≤ 3 x ULN, and albumin ≥ 2.5 g/dL.

10. Serum creatinine performed within 3 weeks prior to starting study therapy must be ≤
1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula
provided in Appendix 11.3) of ≥ 50 mL/minute.

11. Females of childbearing potential must have a negative serum pregnancy test within 24
hours prior to receiving the first dose of study medication. Females of childbearing
potential must agree to use 2 methods of effective contraception or abstain from
heterosexual sex throughout the treatment period and for 5 months after the last dose
of study treatment. Females of childbearing potential are women who have not been
surgically sterilized (have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or have not been free of menses for >1 year.

12. Male subjects with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 7 months after the last
dose of study treatment.

13. Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.

14. An adequate amount of archival tumor tissue must be available at baseline to be
eligible for enrollment in the study. If archival tissue is not available or is
inadequate, then the subject must consent to undergo a mandatory biopsy at baseline in
order to participate in the study.

Exclusion Criteria:

1. Past treatment with an antibody targeting EGFR including cetuximab or panitumumab.

2. Past treatment with an antibody targeting immune checkpoints including CTLA-4, PD-1,
PD-L1, PD-L2, or CD137.

3. Known untreated brain metastasis or brain metastasis treated within 3 months prior to
enrollment in this trial.

4. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

5. Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, or other cancer for which the subject has been disease
free for at least five years.

6. Treatment within 21 days of the first dose of study drug with any other chemotherapy,
immunotherapy, biologic therapy, vaccine therapy, or investigational treatment for the
treatment of malignancy, or failure to recover from adverse effects of prior therapies
administered over 4 weeks prior to Study Day 1. All toxicities from prior therapies
must be ≤ Grade 1 (or ≤ Grade 2 for alopecia or peripheral neuropathy). Prior systemic
treatment in the adjuvant setting is allowed. See note above under inclusion 3.1.8

7. Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent, or compliance to the study procedures.

8. Pregnant or breastfeeding, or planning to become pregnant within 6 months after the
end of treatment. (NOTE: breast milk cannot be stored for future use while the mother
is being treated on study).

9. History of organ allograft or other history of immunodeficiency, or is receiving
systemic steroid therapy or any other form of immunosuppressive therapy within 7 days
before the first dose of investigational treatment.

10. Inability or unwillingness to comply with study and/or follow-up requirements.

11. Any major surgery, extensive radiotherapy, chemotherapy with clinically significant
delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to
randomization and/or daily or weekly chemotherapy without the potential for delayed
toxicity within 14 days prior to randomization.

12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug.

13. Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or Hepatitis C
virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV
infection will be permitted.

14. Active autoimmune disease requiring systemic treatment in the past 3 months (for
example with disease modifying agents, corticosteroids, or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment. Subjects with vitiligo or resolved childhood asthma/atopy would be
an exception to this rule. Subjects that require intermittent use of bronchodilators,
local steroid injections, or inhaled or topical steroids would not be excluded from
the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's
syndrome will not be excluded from the study.

15. Active infection requiring intravenous systemic therapy.