Clinical Trials /

Nivolumab +/- Relatlimab Prior to Chemoradiation With II/III Gastro/Esophageal Cancer

NCT03044613

Description:

Anti-PD-1 (nivolumab) or Anti-PD1/Anti LAG-3- (relaltimab) administration in the pre-operative setting with chemoradiation will be safe and feasible in patients with resectable distal esophageal/gastroesophageal junction cancer and will change cellular and molecular characteristics of the tumor microenvironment that will improve survival.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Esophageal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab or Nivolumab/Ipilimumab Prior to Chemoradiation Plus Nivolumab With II/III Gastro/Esophageal Cancer
  • Official Title: Phase IB Trial of Induction Nivolumab or Nivolumab/Ipilimumab Prior to Concurrent Chemoradiation Plus Nivolumab in Patients With Operable Stage II/III Esophageal/ Gastroesophageal Junction Cancer

Clinical Trial IDs

  • ORG STUDY ID: J1714
  • SECONDARY ID: IRB00122689
  • NCT ID: NCT03044613

Conditions

  • Gastric Cancer
  • Esophageal Cancer
  • GastroEsophageal Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivoArm A
IpilimumabYervoyArm B
CarboplatinParaplat, Paraplatin, Blastocarb, Carboplat, Carbosin, Carbosol, Carbotec, Displata, Ercar, Nealorin, Novoplatinum, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A
PaclitaxelTaxol, Anzatax, Asotax, Bristaxol, Praxel, Taxol KonzentratArm A

Purpose

Anti-PD-1 (nivolumab) or Anti-PD-1/CTLA-4 (ipilimumab) administration in the pre-operative setting and nivolumab combined with chemoradiation will be safe and feasible in patients with resectable distal esophageal/gastroesophageal junction cancer and will change cellular and molecular characteristics of the tumor microenvironment that will improve survival.

Detailed Description

      This is a Phase IB study assessing the safety of 2 cycles of induction (Arm A) nivolumab or
      (Arm B) 1 cycle of induction nivolumab plus ipilimumab prior to concurrent chemoradiation
      plus nivolumab before surgical resection in operable stage II/III
      esophageal/gastroesophageal junction cancer.

      Approximately 32 patients will be enrolled on study with 16 enrolled on Arm A and if no
      unexpected toxicities then an additional 16 patients will be enrolled on Arm B.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalNivolumab 240mg administered IV over 30 minutes every 2 weeks for 2 cycles and then nivolumab 240mg administered IV over 30 minutes every 2 weeks for 3 cycles when given concurrently with standard of care chemoradiation (weekly carboplatin/paclitaxel and concurrent radiation
  • Nivolumab
  • Carboplatin
  • Paclitaxel
Arm BExperimentalNivolumab 1mg/kg administered IV over 30 minutes followed by ipilimumab 3mg/kg administered over 30 minutes on day 1 every 3 weeks for 1 cycle and then nivolumab 240mg administered IV over 30 minutes every 2 weeks for 3 cycles when given concurrently with standard of care chemoradiation (weekly carboplatin/paclitaxel and concurrent radiation).
  • Nivolumab
  • Ipilimumab
  • Carboplatin
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Men and women aged ≥ 18 years old

          -  Histologically proven (squamous cell or adenocarcinoma) esophageal or gastro-
             esophageal junction cancer (core biopsy required).

          -  Stage II/III disease as per AJCC staging 7.0

          -  Baseline imaging with FDG-PET scan and endoscopic ultrasound within 28 days prior to
             registration

          -  ECOG performance status 0-1 (see Appendix B).

          -  Adequate oral intake/nutritional status without the need for enteral or parenteral
             feeding during chemoradiation or preoperative period

          -  Adequate organ function as follows:

               -  Leukocytes ≥ 2,000/mm3

               -  Absolute neutrophil count (ANC) ≥ 1000/mm3

               -  Platelet count ≥ 100,000/mm3

               -  Hemoglobin ≥ 9 g/dL

               -  Creatinine ≤ 2.0 mg/dL

               -  Bilirubin (total) within normal institutional limits (except subjects with
                  Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)

               -  AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 2.5 times the upper limit of
                  normal

               -  PT such that international normalized ratio (INR) is ≤ 1.5 (or an in-range INR,
                  usually between 2 and 3, if a patient is on a stable dose of therapeutic
                  warfarin and a PTT ≤ upper limit of normal

          -  Adequate cardiac function as defined by: no evidence of PR prolongation or AV block
             on baseline electrocardiogram (ECG).

          -  Radiation oncology consultation within 28 days to confirm that disease can be
             encompassed in the radiotherapy field and that normal tissue constraints can be met.

          -  Subjects must have adequate lung function to permit surgical resection determined by
             pre-enrollment pulmonary function tests to include DLCO as follows:

               -  DLCO≥70% predicted OR DLCO<70% but ≥55% with a VO2 max ≥10L/min/kg (assessed by
                  cardiopulmonary exercise testing) or 6 minute walk test ≥500 meters

               -  Subjects with a DLCO<55% are excluded from this study.

               -  Subjects must have a baseline O2 saturation by pulse oximetry that is ≥ 92% both
                  at rest and while walking, off supplemental oxygen

          -  Esophagogastrectomies will be performed via a laparotomy and a right thoracotomy with
             en-bloc removal of perigastric, celiac, periesophageal and subcarinal lymph nodes.
             Esophagogastric reconstruction will be performed above the level of the azygo-caval
             junction using an EEA stapling device.

          -  Either a formalin fixed paraffin block or a minimum of ten 5-micron tissue section's
             (slides) of tumor biopsy sample must be available for biomarker evaluation from
             baseline and repeat EGD.

          -  The effects of nivolumab, on the developing human fetus are unknown. For this reason
             women of child-bearing potential (WOCBP) 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 and for 5 months after the
             last dose of nivolumab. 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. Sexually active fertile men must use effective
             barrier birth control if their partners are WOCBP for 7 months after the last dose of
             nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum
             sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration.

          -  Patient understands the study regimen, its requirements, risks and discomforts and is
             able and willing to sign the informed consent form. Voluntary signed and dated
             IRB/IEC approved written informed consent form in accordance with regulatory and
             institutional guidelines must be obtained before the performance of any protocol
             related procedures that are not part of normal patient care. Subjects must be
             competent to report AEs, understand the drug dosing schedule and use of medications
             to control AEs.

        Exclusion Criteria:

          -  Patient has active, known or suspected autoimmune disease. Subjects with vitiligo,
             type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
             requiring hormone replacement, or conditions not expected to recur in the absence of
             an external trigger are permitted to enroll.

          -  Esophageal tumors that are located in the mid esophagus or higher i.e. not involving
             distal esophagus or GE junction.

          -  Tumors whose proximal end are higher that the level of the carina

          -  Biopsy proven involvement of supraclavicular lymph nodes

          -  Tumors must not extend 5cm or more into the stomach

          -  Patient has a condition requiring systemic treatment with either corticosteroids (>
             10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of first dose. Inhaled or topical steroids and adrenal replacement steroid doses
             are permitted in the absence of active autoimmune disease.

          -  Subjects with previous malignancies (except non-melanoma skin cancers, in situ
             bladder, gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a
             complete remission was achieved at least 1 years prior to study entry and no
             additional therapy (other than adjuvant hormonal therapy for breast cancer) is
             required or anticipated to be required during the study period.

          -  Subjects with brain metastasis are excluded from this study and all patients should
             have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment.

          -  Subjects with a history of interstitial lung disease.

          -  Active systemic infection requiring therapy, positive tests for Hepatitis B surface
             antigen or Hepatitis C ribonucleic acid (RNA).

          -  Known positive history or positive test for Human Immunodeficiency Virus or Acquired
             ImmunoDeficiency Syndrome (AIDS).

          -  History of allergy to study drug components.

          -  Women who are pregnant or nursing.

          -  WOBP and Men with female partners (WOCBP) that are not willing to use contraception.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or
             any other antibody targeting T cell co-regulatory pathways).

          -  Underlying medical conditions that, in the Investigator's opinion, will make the
             administration of study drug hazardous or obscure the interpretation of toxicity or
             adverse events.

          -  Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for
             treatment of either a psychiatric or physical (e.g. infectious disease) illness.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:100 days
Safety Issue:
Description:To investigate the safety of induction nivolumab or nivolumab/ipilimumab administration prior to concurrent chemoradiation/nivolumab in subjects with resectable stage II/III gastro-esophageal junction cancer.

Secondary Outcome Measures

Measure:Feasibility is assessed through the proportion of eligible patients who proceed to surgery without substantial delay (more than 60 days) due to treatment-related reasons
Time Frame:12 weeks
Safety Issue:
Description:To investigate the feasibility of induction nivolumab or nivolumab/ipilimumab prior to concurrent chemoradiation/nivolumab administration in subject's with stage II/III esophageal and gastro-esophageal junction cancer.
Measure:Pathological Complete Response Rate
Time Frame:2 years
Safety Issue:
Description:To determine the pathological complete response rate in patients treated with induction checkpoint inhibition followed by chemo-radiation plus nivolumab prior to surgical resection
Measure:Approximate quantitation of infused nivolumab bound to PD-1 receptors on the surface of T cells in the peripheral blood and within the resected tumor and lymph node specimens
Time Frame:2 years
Safety Issue:
Description:To explore the association between nivolumab +/- ipilimumab exposure and selected pharmacodynamics markers in the peripheral blood and in the tumor microenvironment, including measurement of PD-1 receptor occupancy on tumor infiltrating lymphocytes.
Measure:Changes in Expression of Selected Immune Markers
Time Frame:2 years
Safety Issue:
Description:To measure changes in expression of selected immune markers including changes in the quality and quantity of tumor infiltrating lymphocytes and the T effector to T-Reg ratio compared to baseline, in the blood, primary tumor tissue and draining lymph nodes
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:To assess overall survival in patients receiving neoadjuvant checkpoint inhibitors.
Measure:Recurrence-Free Survival
Time Frame:2 years
Safety Issue:
Description:To assess recurrence-free survival in patients receiving neoadjuvant checkpoint inhibitors

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center

Last Updated

April 5, 2017