CA-4948 in Combination With FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer

Sponsor
Washington University School of Medicine (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05187182
Collaborator
Curis, Inc. (Industry)
42
1
3
50
0.8

Study Details

Study Description

Brief Summary

Based on preclinical data, the investigators hypothesize that IRAK4 inhibition cripples tumor-intrinsic survival signaling and effectively overcomes the desmoplastic and immune-suppressive TME to render chemo- and immunotherapies effective in gastrointestinal (GI) malignancy. Therefore, this trial is designed to evaluate combination of CA-4948 and standard chemo/immunotherapy in untreated gastric and esophageal cancer.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Anticipated Enrollment :
42 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
The dose escalation phase will occur first. In the dose expansion phase, participants will be assigned to either Cohort A or Cohort B and treated in parallel.The dose escalation phase will occur first. In the dose expansion phase, participants will be assigned to either Cohort A or Cohort B and treated in parallel.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I Trial of CA-4948 in Combination With FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer
Anticipated Study Start Date :
Aug 30, 2022
Anticipated Primary Completion Date :
Dec 31, 2025
Anticipated Study Completion Date :
Oct 31, 2026

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose Escalation (CA4948 + FOLFOX + Nivolumab)

CA4948 (dose will depend on dose level assigned) twice daily by mouth. Standard of care mFOLFOX7 every 14 days. Nivolumab every 14 days. Each cycle is 14 days.

Drug: CA-4948
-Provided by Curis, Inc.

Drug: 5-FU
Standard of care part of mFOLFOX7. 2400 mg/m^2 intravenous on Day 1 of each cycle (continuous infusion over 46 hours).

Drug: Leucovorin
Standard of care part of mFOLFOX7. 400 mg/m^2 intravenous on Day 1 of each cycle.

Drug: Oxaliplatin
Standard of care part of mFOLFOX7. 85 mg/m^2 intravenous on Day 1 of each cycle.

Biological: Nivolumab
240 mg intravenous on Day 1 of each cycle
Other Names:
  • Opdivo
  • Experimental: Dose Expansion Cohort A (CA4948 + FOLFOX + Nivolumab)

    CA4948 (dose will be the recommended phase II dose found in the dose escalation portion of study) twice daily by mouth. Standard of care mFOLFOX7 every 14 days. Nivolumab every 14 days. Each cycle is 14 days.

    Drug: CA-4948
    -Provided by Curis, Inc.

    Drug: 5-FU
    Standard of care part of mFOLFOX7. 2400 mg/m^2 intravenous on Day 1 of each cycle (continuous infusion over 46 hours).

    Drug: Leucovorin
    Standard of care part of mFOLFOX7. 400 mg/m^2 intravenous on Day 1 of each cycle.

    Drug: Oxaliplatin
    Standard of care part of mFOLFOX7. 85 mg/m^2 intravenous on Day 1 of each cycle.

    Biological: Nivolumab
    240 mg intravenous on Day 1 of each cycle
    Other Names:
  • Opdivo
  • Experimental: Dose Expansion Cohort B (CA4948 + FOLFOX + Pembrolizumab + Trastuzumab)

    CA4948 (dose will be the recommended phase II dose found in the dose escalation portion of study) twice daily by mouth Standard of care mFOLFOX7 every 14 days. Pembrolizumab every 21 days. Trastuzumab every 21 days. Each cycle is 42 days.

    Drug: CA-4948
    -Provided by Curis, Inc.

    Drug: 5-FU
    Standard of care part of mFOLFOX7. 2400 mg/m^2 intravenous on Day 1 of each cycle (continuous infusion over 46 hours).

    Drug: Leucovorin
    Standard of care part of mFOLFOX7. 400 mg/m^2 intravenous on Day 1 of each cycle.

    Drug: Oxaliplatin
    Standard of care part of mFOLFOX7. 85 mg/m^2 intravenous on Day 1 of each cycle.

    Biological: Pembrolizumab
    200 mg intravenous on Days 1 and 22 of each cycle. May be transitioned to 400 mg intravenous on Day 1 of each cycle beginning with Cycle 2 at the discretion of the treating physician. Dosing may continue for a max of 2 years.
    Other Names:
  • Keytruda
  • Drug: Trastuzumab
    8 mg/kg intravenous loading dose on Cycle 1 Day 1. 6 mg/kg intravenous on Cycle 1 Day 22 and on Days 1 and 22 of each cycle thereafter. May be transitioned to 4 mg/kg on Days 1, 15, and 29 of each cycle beginning with Cycle 2 at the discretion of the treating physician.
    Other Names:
  • Herceptin
  • Outcome Measures

    Primary Outcome Measures

    1. Safety of regimen as measured by number of adverse events [From start of treatment through 60 days post last CA-4948 dose (estimated to be 16 months)]

    2. Recommended phase II dose of CA-4948 in combination with FOLFOX/PD-1 inhibitor with/without trastuzumab [Completion of 2 cycles (each cycle is 14 days) for all participants enrolled in Dose Escalation portion of the study (estimated to be 19 months)]

      -The recommended phase II dose will be determined based on the acceptable rate of dose-limiting toxicities and maximum tolerated dose to be most appropriate to evaluate in the phase 2 study.

    Secondary Outcome Measures

    1. Progression-free rate (PFR) [At 6 months]

      Proportion of participants with no disease progression Progressive disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

    2. Disease control rate (DCR) [At 6 months post study completion (estimated to be 20 months)]

      Proportion of participants who had complete response, partial response, or stable disease by RECIST 1.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

    3. Overall response rate (ORR) [Through completion of treatment (estimated to be 14 months)]

      Defined as number of participants with complete response or partial response per RECIST 1.1 guidelines. Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

    4. Progression-free survival (PFS) [At 1 year post study completion (estimated to be 26 months)]

      PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. The alive patients without progression are censored at the date of last follow-up. Progressive disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

    5. Overall survival (OS) [At 1 year post study completion (estimated to be 26 months)]

      -OS is defined as the duration of time from start of treatment to time of death from any cause. The alive patients are censored at the date of last follow-up.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Advanced unresectable or metastatic histologically or cytologically confirmed adenocarcinoma or squamous cell carcinoma of the stomach, gastroesophageal junction, or esophagus

    • Measurable or evaluable disease defined by RECIST 1.1.

    • Expansion cohorts only: Lesions amenable to research biopsy. This criteria can be waived by the PI after documented discussion with the treating physician.

    • Known HER2 status if histology is adenocarcinoma prior to enrollment; results from local CLIA laboratory is acceptable.

    • For Dose Escalation, patients are required to have documented HER2 negative cancer.

    • For Dose Expansion, patients will be enrolled to either HER2 positive or negative cohorts at the time of enrollment

    • No prior systemic treatment for unresectable/advanced gastric, GEJ, or esophageal cancer.

    • Neoadjuvant or adjuvant systemic therapy is allowed; however, surgical resection should have been > 12 months from planned C1D1.

    • Definitive chemoradiation is allowed if the last date of chemotherapy or radiation (whichever is more recent) is > 3 months from planned C1D1.

    • Prior palliative radiation therapy, including brain radiation, in the unresectable setting is allowed, but the last treatment date should be >10 days from planned C1D1.

    • At least 18 years of age

    • ECOG performance status 0 or 1

    • Normal bone marrow and organ function as defined below:

    • Absolute neutrophil count ≥ 1,500/mcl

    • Platelets ≥ 100,000/mcl

    • Hemoglobin ≥ 9.0 g/dL

    • Total bilirubin ≤ 1.5 x IULN

    • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN

    • Creatinine ≤ 1.5 x IULN or creatinine clearance > 50 mL/min by Cockcroft-Gault

    • Expansion Cohort B patients only: LVEF above LLN as assessed by MUGA or ECHO

    • The effects of CA-4948 on the developing human fetus are unknown. For this reason, women of childbearing 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 participating in this study, she must 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 the study, and 3 months after completion of the study

    • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

    Exclusion Criteria:
    • Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment. Use of medical marijuana is permitted.

    • A history of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of metastatic gastric, GEJ, or esophageal cancer.

    • History of allogeneic organ or stem cell transplant

    • Currently receiving any other investigational therapeutic agents. Investigational tracers related to imaging studies are allowed with a 7 day-washout.

    • Clinically active CNS metastasis; treated and asymptomatic metastasis allowed at the discretion of the PI. Radiotherapy to the brain must be completed > 10 days prior to planned C1D1.

    • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948, FOLFOX, nivolumab, trastuzumab or other agents used in the study.

    • Concomitant use of drugs with a known risk of causing prolonged QTc and/or Torsades de Pointes or a history of risk factors for Torsades de Pointes.

    • Presence of interstitial lung disease or pneumonitis ≥ G2

    • Administration of a live attenuated vaccine within 30 days prior to enrollment.

    • QTc (Bazett) >470ms on screening EKG

    • Gastrointestinal condition which could impair absorption of CA-4948 or inability to ingest CA-4948

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia

    • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry.

    • Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended. Recommend exclusion of specific ART agents based on predicted drug-drug interactions (i.e., for sensitive CYP3A4 substrates, concurrent strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers (efavirenz) should be contraindicated).

    • Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid participants with a history of Grave's disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll after discussing with the PI.

    • Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study treatment except for adrenal replacement steroid doses > 10 mg daily prednisone equivalent in the absence of active autoimmune disease. Note: treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating study treatment is permitted. Inhaled intranasal, intra-articular, and topical steroid uses are permitted.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Washington University School of Medicine Saint Louis Missouri United States 63110

    Sponsors and Collaborators

    • Washington University School of Medicine
    • Curis, Inc.

    Investigators

    • Principal Investigator: Kian-Huat Lim, M.D., Ph.D., Washington University School of Medicine

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Washington University School of Medicine
    ClinicalTrials.gov Identifier:
    NCT05187182
    Other Study ID Numbers:
    • 202202027
    First Posted:
    Jan 11, 2022
    Last Update Posted:
    Jun 28, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 28, 2022