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Colorectal Neoplasms MalignantPhase 1NCT03507699

Combined Immunotherapy and Radiosurgery for Metastatic Colorectal Cancer

A Phase 1 study testing Liver radiation therapy, Nivolumab Injection [Opdivo] and Ipilimumab Injection [Yervoy] in people with Colorectal Neoplasms Malignant and Liver Metastases, run by Sheba Medical Center at 1 site in Israel.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Liver radiation therapy, Nivolumab Injection [Opdivo] and Ipilimumab Injection [Yervoy]
Could I receive a placebo?
No, everyone receives an active treatment
How many people
19 participants
Where
1 siteIsrael
Study dates
15 Dec 2018to 25 May 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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.
Show all 31Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

Israel1 site

  • Sheba Medical Center

    Ramat Gan, 52621

Other trials in Israel

About this study

Official title: Combination Treatment of Nivolumab, Ipilimumab, Intratumoral CMP-001 and Radiosurgery for Liver Metastases in Colorectal Carcinoma

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.

Read the detailed description

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.

Being tested
Liver radiation therapy, Nivolumab Injection [Opdivo], Ipilimumab Injection [Yervoy], CMP-001
Keywords
radiotherapy, radiosurgery, immunotherapy, PD-1, CTLA-4, TLR9
Medical subject headings
Colonic Neoplasms, Diabetes Mellitus, Insulin-Dependent, 12

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Liver radiation therapyRadiation

    Also called Liver radiosurgery

    21 Gy in three fractions to one liver metastasis

  • Nivolumab Injection [Opdivo]Drug

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

  • Ipilimumab Injection [Yervoy]Drug

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

  • CMP-001Drug

    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.

Study groups in NCT03507699
Study groupRoleWhat they receive
Immunotherapy aloneExperimentalNivolumab 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.
Receives: Drug: Nivolumab Injection [Opdivo]; Drug: Ipilimumab Injection [Yervoy]; Drug: CMP-001
Combined radiotherapy and immunotherapyExperimentalLiver 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.
Receives: Radiation: Liver radiation therapy; Drug: Nivolumab Injection [Opdivo]; Drug: Ipilimumab Injection [Yervoy]; Drug: CMP-001

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

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

Secondary outcomes (2)

  1. Response rate as assessed by RECIST v1.1

    To evaluate the objective tumor response rate (ORR; including complete response, CR, or partial response, PR) from a combination treatment with nivolumab, ipilimumab, CMP-001 and radiosurgery as assessed by RECIST v1.1. Of note, the irradiated and injected lesion will not be used for RECIST v1.1 analysis.

    Measured: assessed at week 10, week 18, and week 24

  2. Progression free survival

    To evaluate the progression free survival (PFS) for treatment with a combination of nivolumab, ipilimumab, CMP-001 and radiosurgery defined as the time from first dose until disease progression or death (or date of last documentation of being alive), respectively.

    Measured: from time of first dose for 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Apr 2018
  2. Study start15 Dec 2018
  3. Primary completion18 Aug 2021
  4. Study completion25 May 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
a phase I inter-patient dose-escalation study.
Masking
None (open label)
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03507699
Sponsor's protocol ID
4465-17-SMC
Other IDs
CA209-991
Status last verified
Apr 2023
First submitted
9 Apr 2018
Last updated
18 Apr 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Liver radiation therapy, Nivolumab Injection [Opdivo] and Ipilimumab Injection [Yervoy] in people with Colorectal Neoplasms Malignant and Liver Metastases, run by Sheba Medical Center at 1 site in Israel.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of participants with serious dose-limiting treatment-related adverse events as assessed by CTCAE v5.0 (time frame: The dose-limiting toxicity period lasts from day 1 until day 42 inclusive). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03507699.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2023.

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