Combined Immunotherapy and Radiosurgery for Metastatic Colorectal Cancer

NCT03507699 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 4465-17-SMCCA209-991
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Colorectal Neoplasms Malignant; Liver Metastases

Keywords

radiotherapy; radiosurgery; immunotherapy; PD-1; CTLA-4; TLR9

Outcome Measures

Primary Outcomes (1)

• Number of participants with serious dose-limiting treatment-related adverse events as assessed by CTCAE v5.0

  Dose-Limiting Toxicities (DLTs) are defined below and only include AEs that are considered possibly, probably, or definitely related to the CMP-001, nivolumab or ipilimumab treatments which occur during the first 42 days of therapy, starting from completion of SBRT (day 1). The following AEs will be considered DLTs if deemed related to study therapy: Hematologic * Grade 4 neutropenia * Febrile neutropenia, defined as absolute neutrophil count (ANC) \<1000/mm3 with a temperature of 38.3 degrees Celsius. * Grade 3 neutropenic infection * Grade 3 thrombocytopenia with bleeding * Grade 4 thrombocytopenia Non-hematologic: * Grade 3 toxicities (non-laboratory) * Grade 3 nausea, vomiting or diarrhea despite maximal medical intervention * Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) Other (non AST/ALT) non-hematologic G 3 laboratory value if the abnormality leads to overnight hospitalization

  The dose-limiting toxicity period lasts from day 1 until day 42 inclusive

Secondary Outcomes (2)

• Response rate as assessed by RECIST v1.1

  assessed at week 10, week 18, and week 24

• Progression free survival

  from time of first dose for 24 months

Study Arms (2)

Immunotherapy alone

EXPERIMENTAL

Nivolumab will be administered at a dose of 3mg/kg every 2 weeks. Ipilimumab will be administered at a dose of 1mg/kg every 6 weeks. CMP-001 will be administered both into the liver metastasis (once), and also injected subcutaneously (four times, over six weeks) at a dose of 5-10 mg.

Drug: Nivolumab Injection [Opdivo]; Drug: Ipilimumab Injection [Yervoy]; Drug: CMP-001

Combined radiotherapy and immunotherapy

EXPERIMENTAL

Liver radiation therapy: three treatments to one liver metastasis, administered on alternate days. Nivolumab will be administered at a dose of 3mg/kg every 2 weeks. Ipilimumab will be administered at a dose of 1mg/kg every 6 weeks. CMP-001 will be administered both into the liver metastasis (once), and also injected subcutaneously (four times, over six weeks) at a dose of 5-10 mg.

Radiation: Liver radiation therapy; Drug: Nivolumab Injection [Opdivo]; Drug: Ipilimumab Injection [Yervoy]; Drug: CMP-001

Interventions

Liver radiation therapy RADIATION

21 Gy in three fractions to one liver metastasis

Also known as: Liver radiosurgery

Combined radiotherapy and immunotherapy

Nivolumab Injection [Opdivo] DRUG

administered IV at a dose of 3mg/kg every 2 weeks

Combined radiotherapy and immunotherapy; Immunotherapy alone

Ipilimumab Injection [Yervoy] DRUG

administered IV at a dose of 1mg/kg every 6 weeks

Combined radiotherapy and immunotherapy; Immunotherapy alone

CMP-001 DRUG

A TLR9 agonist, will be administered both into the liver metastasis (three times), and also injected subcutaneously at a dose of 5-10 mg every two weeks.

Combined radiotherapy and immunotherapy; Immunotherapy alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sheba Medical Center: lead
• Checkmate Pharmaceuticals: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Sheba Medical Center

Ramat Gan, 52621, Israel

Location

MeSH Terms

Conditions

Colonic Neoplasms; Diabetes Mellitus, Insulin-Dependent, 12

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice Chair, and Director, Center for Translational Research in Radiation Oncology Dep. Radiation Oncology

Model Details: a phase I inter-patient dose-escalation study.

Study Record Dates

• First Submitted: April 9, 2018
• First Posted: April 25, 2018
• Study Start: December 15, 2018
• Primary Completion: August 18, 2021
• Study Completion: May 25, 2022
• Last Updated: April 18, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)