Combined Immunotherapy and Radiosurgery for Metastatic Colorectal Cancer
Combined Immunotherapy and Radiosurgery for Metastatic Colorectal Cancer
A single institution study to evaluate the safety and tolerability of the combination
 treatment of nivolumab, ipilimumab, CMP-001 and radiosurgery in patients with metastatic
 colorectal cancer with liver metastases.
Patients will be treated with radiosurgery to liver metastases (completed by day 1), followed
 by a priming dose of subcutaneous CMP-001 (day 1 ± 4 days), intratumoral injections of
 CMP-001 on days 13, 36 and 55, combined with nivolumab 3mg/kg every 2 weeks (start day 15)
 and ipilimumab 1 mg/kg every 6 weeks (start day 15). From day 71 biweekly subcutaneous
 injections of CMP-001 will commence. Nivolumab, ipilimumab and subcutaneous injections of
 CMP-001 will be continued until disease progression or up to 24 months in the absence of
 disease progression or unacceptable toxicity. Two research biopsies will be taken from a
 liver metastasis. The first biopsy will be taken during the screening period (pretreatment)
 and the second one 5 weeks post-radiosurgery (which is 3 weeks post-initiation of nivolumab /
 ipilimumab). As a safety run-in, the initial cohort of 3-6 patients will not receive
 radiosurgery. The next cohort will not commence until the last patient from the initial
 cohort has been followed up for at least 8 weeks post first intratumoral injection. Efficacy
 endpoints will be based upon a non-irradiated lesion.
Inclusion Criteria:

 Disease factors

 -  Histologically- or cytologically-confirmed diagnosis of colorectal cancer (CRC).

 -  Metastatic or recurrent CRC, deemed surgically or medically unresectable.

 -  Subjects have received two or more standard available therapies known to prolong
 survival and for which they would be considered eligible, whether in adjuvant or
 metastatic setting. Such therapies should include regimens containing oxaliplatin and
 irinotecan in combination with a fluoropyrimidine, if appropriate (e.g., FOLFOX and
 FOLFIRI, or their variants). Subjects that are unable to receive oxaliplatin and/or
 irinotecan due to allergy or hypersensitivity, or due to concerns regarding the side
 effects of oxaliplatin and/or irinotecan, will be allowed to receive less than two
 lines of standard therapies prior to enrollment to this study.

 -  Patients must have at least two liver metastases, separated by ≥2 cm, and measured in
 at least one dimension (longest diameter) as ≥2 cm by CT/MRI. One of the metastases
 must be amenable to biopsy and SBRT.

 General considerations

 -  Age ≥18 years.

 -  ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A).

 -  Life expectancy of ≥ 3 months

 -  Patients must have normal organ and marrow function as defined below:

 -  absolute neutrophil count ≥1,500/mcL

 -  platelets ≥100,000/mcL

 -  hemoglobin ≥ 9.0 g/dL

 -  total bilirubin ≤ 1.5 x ULN except subjects with Gilbert Syndrome who must have a
 total bilirubin level < 3.0 mg/dL).

 -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

 -  creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min (using the
 Cockcroft Gault formula)

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry and for
 the duration of study participation. Should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately. Men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 4 months after completion of treatment.

 -  Signed Written Informed Consent

 -  Subjects must have signed and dated an IRB approved written informed consent form in
 accordance with regulatory and institutional guidelines. This must be obtained before
 the performance of any protocol related procedures that are not part of normal subject
 care.

 -  Subjects must be willing and able to comply with scheduled visits, treatment schedule,
 and laboratory testing.

 Exclusion Criteria:

 Disease factors / Tumor characteristics

 -  Has an MSI-H phenotype or a known MMR deficiency.

 -  Has known active central nervous system (CNS) metastases and/or carcinomatous
 meningitis. Subjects with previously treated brain metastases may participate provided
 they are stable (without evidence of progression by imaging for at least four weeks
 prior to the first dose of trial treatment and any neurologic symptoms have returned
 to baseline), have no evidence of new or enlarging brain metastases, and are not using
 steroids for at least 7 days prior to trial treatment.

 Previous treatments and trials

 -  Is currently participating in or has participated in a study of an investigational
 agent or using an investigational device within 3 weeks of the first dose of
 treatment.

 -  Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
 recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
 administered more than 4 weeks earlier.

 -  Has had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to
 study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse
 events due to a previously administered agent.° Note: Subjects with ≤ Grade 2
 neuropathy are an exception to this criterion and may qualify for the study.

 -  If subject received major surgery, they must have recovered adequately from the
 toxicity and/or complications from the intervention prior to starting therapy.

 Comorbidities, medications and immune modulation agents

 -  Has a known additional malignancy that is progressing or requires active treatment.
 Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
 skin, or in situ cervical cancer that has undergone potentially curative therapy.

 -  Has an active autoimmune disease requiring systemic treatment within the past 3 months
 or a documented history of clinically severe autoimmune disease, or a syndrome that
 requires systemic steroids or immunosuppressive agents. Subjects with type I diabetes
 mellitus, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
 systemic treatment, or conditions not expected to recur in the absence of an external
 trigger are permitted to enroll. Subjects that require intermittent use of
 bronchodilators or local steroids, e.g., inhaled or topical steroids, at a dose of
 less than the equivalent of 10mg prednisone daily, would not be excluded from the
 study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's
 syndrome will not be excluded from the study.

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

 -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the trial, interfere with the subject's
 participation for the full duration of the trial, or is not in the best interest of
 the subject to participate, in the opinion of the treating investigator.

 -  Has known psychiatric or substance abuse disorders that would interfere with
 cooperation with the requirements of the trial.

 -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
 projected duration of the trial, starting with the pre-screening or screening visit
 through 120 days after the last dose of trial treatment.

 -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
 other form of immunosuppressive therapy within 7 days prior to the first dose of trial
 treatment.

 -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

 -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
 [qualitative] is detected).

 -  Has received a live vaccine within 30 days prior to the first dose of trial treatment.

 -  Known medical condition that, in the investigator's opinion, would increase the risk
 associated with study participation or study drug administration or interfere with the
 interpretation of safety results.

 -  History of allergy or hypersensitivity to any study drug components, to compounds of
 similar chemical or biologic composition

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection requiring systemic therapy, symptomatic congestive heart failure, unstable
 angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
 would limit compliance with study requirements.

 -  Previous stem cell transplant.

 -  Significant bleeding event within the last 12 months that places the patient at risk
 for intrahepatic IT injection procedure based on Investigator assessment.

 -  Anticoagulant or anti-platelet medication that cannot be interrupted prior to CMP-001
 intratumoral injection, including:

 -  Aspirin that cannot be discontinued for 7 days prior to CMP-001 intratumoral
 injection.

 -  Coumadin that cannot be discontinued for 7 days prior to CMP-001 intratumoral
 injection.

 -  Low molecular weight heparin (LMWH) that cannot be discontinued >24 hours prior
 to CMP-001 intratumoral injection.

 -  Unfractionated heparin (UFH) that cannot be discontinued >4 hours prior to
 CMP-001 intratumoral injection.

 -  Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor
 (rivaroxaban, apixiban, and endoxaban) that cannot be discontinued for 4 days
 prior to CMP-001 intratumoral injection.

 -  NOTE: LMWH or UFH may be used to transition patients on and off of the above
 anti-coagulants (if deemed appropriate by the treating physician) prior to
 CMP-001 intratumoral injection as long as the last dose of LMWH is administered
 >24 hours prior to treatments and last dose of UFH is administered >4 hours prior
 to treatments.