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Colorectal NeoplasmPhase 1NCT02991196

Antibody DS-8273a Administered in Combination With Nivolumab in Subjects With Advanced Colorectal Cancer

A Phase 1 study testing DS-8273a + nivolumab in people with Colorectal Neoplasm, run by Daiichi Sankyo at 4 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This trial is being performed in two parts: Dose Escalation and Dose Expansion. The primary objective for the Dose Escalation part is to determine the safety and tolerability at different doses of DS-8273a administered in combination with nivolumab and to identify the dose combination for the Dose Expansion cohort in… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Neoplasm
What is being tested?
DS-8273a + nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
4 sitesUnited States
Study dates
1 Dec 2016to 22 Sep 2017
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

  • A pathologically documented colorectal cancer that:
  • Is unresectable or metastatic
  • Has undergone ≥ 2 prior standard therapies
  • Is MMR-proficient [selected by the site based on microsatellite instability assay (MSI) and/or immunohistochemistry (IHC) for MMR proteins]
  • At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
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  • Peripheral blood MDSC level ≥ 10% of mononuclear cell fraction (assayed at a central laboratory)
  • Adequate bone marrow, renal, hepatic, and blood clotting function
  • Able to comply with protocol visits and procedures
  • Agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study (women for 23 weeks and men for 31 weeks after the last dose of study drug)
  • Are fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Institutional Review Board (IRB)-approved informed consent form (ICF), including Health Insurance Portability and Accountability Act authorization, if applicable, before performance of any study-specific procedures or tests
  • Are willing to provide available pre-existing diagnostic or resected tumor samples. Providing fresh tumor biopsies are optional for all subjects in Dose Escalation cohorts. In the Dose Expansion cohort, up to 6 subjects may be requested to provide pre- and post-treatment tumor biopsies based on eligibility for the procedure. For those subjects who do not have an MMR status, inclusion in the Dose Escalation and Dose Expansion can be achieved by providing a fresh tumor biopsy for MMR testing.
  • Subjects with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study. Inhaled steroids and intra-articular steroid injections are permitted in this study.

Who cannot join

  • Active infection or chronic comorbidity that would interfere with therapy
  • History of other malignancy(ies), except adequately treated non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated, with no evidence of disease for ≥ 3 years.
  • History of severe hypersensitivity reactions to other monoclonal antibodies.
  • Any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that requires concomitant use of chronic systemic corticosteroids or other immunosuppressive medications, except for subjects with vitiligo, treated thyroiditis or resolved asthma/atopy.
  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody (or any other antibody targeting T-cell co-stimulation pathways).
  • Tested positive for hepatitis B or C serological markers (hepatitis B surface antigen or antibodies to hepatitis C virus) or human immunodeficiency virus.
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  • Recipient of vaccines within 1 month of or during study drug treatment.
  • Requires daily supplemental oxygen.
  • Recipient of a stem cell or bone marrow transplant.
  • A concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator or Sponsor.
  • Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.
  • Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy).
  • Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy).
  • Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment with small-molecule targeted agents within 2 weeks, or 5 half-lives before study drug treatment, whichever is longer.
  • Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment.
  • Participation in a therapeutic clinical study within 3 weeks before study drug treatment (for small-molecule targeted agents, this non-participation period is 2 weeks or 5 half-lives, whichever is longer), or current participation in other investigational procedures.
  • Pregnant or breastfeeding, or planning to become pregnant.
  • Substance abuse or medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
  • Life expectancy < 3 months, in the opinion of the Investigator.

Trial locations and contacts

4 sites in 1 country.

United States4 sites
  • South Texas Accelerated Research Therapeutics (START) Midwest

    Grand Rapids, Michigan, 49503

  • MD Anderson Cancer Center

    Houston, Texas, 77030-4009

  • South Texas Accelerated Research Therapeutics, LLC (START)

    San Antonio, Texas, 78229

  • Georgetown University Medical Center

    Washington D.C., District of Columbia, 20007

Other trials in United States

About this study

Official title: A Phase 1 Study of TRAIL-R2 (DR5) Antibody DS-8273a Administered in Combination With Nivolumab in Subjects With Advanced Colorectal Cancer

This trial is being performed in two parts: Dose Escalation and Dose Expansion.

The primary objective for the Dose Escalation part is to determine the safety and tolerability at different doses of DS-8273a administered in combination with nivolumab and to identify the dose combination for the Dose Expansion cohort in subjects with mismatch repair (MMR)-proficient advanced colorectal cancer.

Read more

The primary objectives for the Dose Expansion part are:

  • To further evaluate the safety and tolerability of DS-8273a administered at the selected dose in combination with nivolumab in subjects with MMR-proficient advanced colorectal cancer
  • To evaluate preliminary anti-tumor activity of DS-8273a plus nivolumab administered at the selected dose in subjects with MMR-proficient advanced colorectal cancer
Being tested
DS-8273a + nivolumab
Keywords
Advanced colorectal cancer, DNA mismatch repair (MMR), MMR-proficient Subjects, TRAIL-R2 (DR5) Antibody
Medical subject headings
Colorectal Neoplasms

What participants receive

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

  • DS-8273a + nivolumabDrug

    Nivolumab will be administered at 240 mg intravenously (IV) once every two weeks (Q2W) over 30 (± 5) minutes (on Days 1 and 15 of each cycle of 28 days). DS-8273a will be administered [90 (± 15) minutes on Day 1 of Cycle 1, and 60 (± 15) minutes in subsequent infusions] after the end of the nivolumab infusion in ascending doses up to 1200 mg IV Q2W. The regimen is adjusted based on injection site reactions or adverse events. Additional dose combinations may be considered based on the assessment of safety, primary pharmacodynamic (PDy) effects, and preliminary anti-tumor activities.

Study groups in NCT02991196
Study groupRoleWhat they receive
DS-8273a + nivolumabExperimentalParticipants will receive their treatment dose until discontinuation for any reason, or trial completion, within two years
Receives: Drug: DS-8273a + nivolumab

What is being measured

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

  1. Dose Escalation Part: Number of Participants with Dose-Limiting Toxicities (DLT)

    A DLT is defined as a study drug-related ≥ Grade 3 Adverse Event (AE) occurring during the first cycle (28 days) of treatment, with specific exceptions for hematologic events, elevations in hepatic function enzymes, and adverse events that are pre-identified as not being DLTs.

    Measured: During the first treatment cycle (28 days)

  2. Dose Escalation and Dose Expansion Parts: Number of Participants with Clinically Significant Safety Parameters

    Safety parameters will include adverse events that are serious (SAEs), treatment emergent (TEAEs), dose-limiting toxicities (DLTs), physical examination findings (including Eastern Cooperative Oncology Group [ECOG] Performance Status), vital sign measurements, clinical laboratory parameters (serum chemistry, hematology, and urinalysis), immune-related (ir) adverse events (irAEs), anti-drug antibody (ADA), and electrocardiogram (ECG) parameters.

    Measured: 2 years

  3. Dose Escalation Part: Maximum Tolerated Dose (MTD)

    The MTD is defined as the highest dose of DS-8273a in combination with the tested dose of nivolumab that results in a DLT in less than one-third of the subjects enrolled at that dose level of at least 6 evaluable subjects. However, AEs that meet the definition of DLT appearing at later cycles will also be considered for the determination of MTD and selection of the Dose Expansion dose. If the MTD is not reached at 1200 mg of DS-8273a IV Q2W, this highest tested dose may be selected as the maximum administered dose (MAD).

    Measured: 2 years

  4. Dose Expansion Part: Overall Objective Response Rate (per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1)

    The overall objective response rate (ORR) is defined as the number of subjects whose Best Overall Response is either a Complete Response (CR) or Partial Response (PR), divided by the total number of treated subjects with at least one post-baseline tumor assessment.

    Measured: 2 years

  5. Dose Expansion Part: Number of Participants in each Category of Best Overall Response (per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1)

    Categories: CR, PR, Stable Disease (SD), Progressive Disease (PD)

    Measured: 2 years

  6. Dose Expansion Part: Disease Control Rate (DCR) for 6 Months

    DCR for 6 months defined as the number of subjects with CR, PR, or SD for 6 months divided by the total number of treated subjects with at least 1 post-baseline tumor assessment

    Measured: 6 months

  7. Dose Expansion Part: Number of Participants with Progression-Free Survival (PFS)

    PFS is defined as survival without disease progression

    Measured: 2 years

  8. Dose Expansion Part: Time to Progression (TTP)

    Mean TTP within 2 years

    Measured: within 2 years

  9. Dose Expansion Part: Duration of Response

    Duration of response for those subjects with a Best Overall Response of CR or PR

    Measured: within 2 years

  10. Dose Escalation Part: Number of Participants with Immune-related Response (per Criteria Modified from RECIST Version 1.1 [irRECIST])

    Criteria include:

    • Immune-related (ir) Best Overall Response with response categories of irCR, irPR, irSD, irPD
    • Immune-related ORR (irORR) defined as the number of subjects whose Best Overall Response is either an irCR or irPR divided by the total number of treated subjects with at least 1 post-baseline tumor assessment
    • Duration of immune-related-response for those subjects with immune-related Best Overall Response of irCR or irPR
    • Immune-related DCR (irDCR) for 6 months defined as the number of subjects with irCR, irPR, or irSD for 6 months divided by the total number of treated subjects with at least 1 post-baseline tumor assessment
    • Immune-related PFS
    • Immune-related TTP

    Measured: 2 years

Secondary outcomes (2)
  1. Plasma Concentrations of DS-8273a

    The plasma concentrations of DS-8273a may be used to assess the exposure levels and for population pharmacokinetic (PK) analysis, if feasible, but no PK parameters will be calculated from the concentrations collected from this study due to sparse sampling time points.

    Measured: Before and at the end of the first 3 infusions (Cycle 1 Days 1 and 15, and Cycle 2 Day 1), a single time point on Cycle 1 Day 8, then every 16 weeks on the same days as ADA sample analysis, and at the last Visit (if not collected within prior 16 weeks)

  2. Number of Participants with Primary Pharmacodynamic (PDy) Effects of the Combination Regimen on Myeloid-Derived Suppressor Cells (MDSCs) and their Subsets in Peripheral Blood

    Subset Categories: Polymorphonuclear (PMN)-type and Monocytic-MDSCs (M-MDSCs)

    Measured: 2 years

Timeline

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

  1. First posted13 Dec 2016 (estimated)
  2. Study start1 Dec 2016
  3. Primary completion22 Sep 2017
  4. Study completion22 Sep 2017

Why it stopped: Business Decision

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
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02991196
Sponsor's protocol ID
DS8273-A-U103
Other IDs
Protocol ID CA209-860
Status last verified
Sep 2017
First submitted
8 Dec 2016
Last updated
12 Feb 2019
Results posted
No
Individual data sharing
Yes: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing DS-8273a + nivolumab in people with Colorectal Neoplasm, run by Daiichi Sankyo at 4 sites in United States.

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 13 inclusion and 19 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: stopped early, as of the sponsor's last update on 12 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. 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 was stopped early (reason given: Business Decision). Results are not available in the source record.

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?

Dose Escalation Part: Number of Participants with Dose-Limiting Toxicities (DLT) (time frame: During the first treatment cycle (28 days)). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
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 12 Feb 2019.

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