Clinical Trials /

IRX-2, Cyclophosphamide, and Pembrolizumab in Treating Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Cancer

NCT03918499

Description:

This phase Ib/II trial studies the side effects of IRX-2, cyclophosphamide, and pembrolizumab work in treating participants with gastric or gastroesophageal junction cancer that has come back or that has spread to other places in the body. Interleukins, such as those found in IRX-2, are proteins made by white blood cells and other cells in the body and may help regulate immune response. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving RX-2, cyclophosphamide, and pembrolizumab may work better in treating participants with gastric or gastroesophageal junction cancer.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: IRX-2, Cyclophosphamide, and Pembrolizumab in Treating Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Cancer
  • Official Title: A Phase 1b/2 Trial of the IRX-2 Regimen and Pembrolizumab in Patients With Advanced Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 18069
  • SECONDARY ID: NCI-2018-01885
  • SECONDARY ID: 18069
  • NCT ID: NCT03918499

Conditions

  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Metastatic Gastric Adenocarcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Recurrent Gastric Adenocarcinoma
  • Recurrent Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (pembrolizumab, cyclophosphamide, and IRX-2)
Cytokine-based Biologic Agent IRX-2IRX-2Treatment (pembrolizumab, cyclophosphamide, and IRX-2)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, cyclophosphamide, and IRX-2)

Purpose

This phase Ib/II trial studies the side effects of IRX-2, cyclophosphamide, and pembrolizumab work in treating participants with gastric or gastroesophageal junction cancer that has come back or that has spread to other places in the body. Interleukins, such as those found in IRX-2, are proteins made by white blood cells and other cells in the body and may help regulate immune response. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving RX-2, cyclophosphamide, and pembrolizumab may work better in treating participants with gastric or gastroesophageal junction cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety profile of combination IRX‐2 regimen and pembrolizumab.

      SECONDARY OBJECTIVES:

      I. To evaluate the overall response rate of IRX‐2 regimen combined with pembrolizumab using
      Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune modified RECIST
      criteria.

      II. To evaluate initial median progression‐free and overall survival in these patients
      treated with combination IRX‐2 regimen and pembrolizumab.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the circulating T cell profiles in patients before and after therapy with
      combination IRX‐2 regimen and pembrolizumab.

      II. To evaluate the baseline and post‐treatment tumor tissue immune gene expression profiling
      using the Nanostring platform.

      III. To explore identification of tumor tissue neoantigens through a multiplex proteomic
      assay (MHC‐PepSeq) paired with tumor genomic and transcriptomic sequencing.

      IV. To explore putative biomarkers (including circulating tumor deoxyribonucleic acid [DNA]
      and immune cell profiles) in peripheral blood to generate hypotheses for response to
      treatment with combination IRX‐2 regimen and pembrolizumab.

      OUTLINE:

      Participants receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Participants
      also receive cyclophosphamide IV on day 1 and IRX‐2 subcutaneously (SC) for 10 days starting
      on day 4 during cycles 1, 5, 9, 13, 17, 21, 25, 29, and 33. Treatment repeats every 3 weeks
      for up to 35 cycles in the absence of disease or unacceptable toxicity.

      After completion of study treatment, participants are followed up for 30 days and then up to
      1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, cyclophosphamide, and IRX-2)ExperimentalParticipants receive pembrolizumab IV over 30 minutes on day 1. Participants also receive cyclophosphamide IV on day 1 and IRX‐2 SC for 10 days starting on day 4 during cycles 1, 5, 9, 13, 17, 21, 25, 29, and 33. Treatment repeats every 3 weeks for up to 35 cycles in the absence of disease or unacceptable toxicity.
  • Cyclophosphamide
  • Cytokine-based Biologic Agent IRX-2
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologically or cytologically confirmed recurrent or metastatic
             gastric or gastroesophageal junction (GEJ) adenocarcinoma progressed or intolerant to
             >= 2 lines of systemic therapy.

          -  Patients must have recurrent or metastatic gastric/GEJ adenocarcinoma that are not
             amenable to local therapy with curative intent (surgery or radiation therapy with or
             without chemotherapy).

          -  Willing and able to give informed consent and adhere to protocol therapy; written
             informed consent and any locally required authorization must be obtained from the
             patient prior to performing any protocol‐related procedures, including screening
             evaluations.

          -  No prior exposure to PD‐1/PD‐L 1 inhibitor therapy.

          -  Patients are deemed eligible for pembrolizumab therapy with tumors demonstrating PD‐L1
             expression by the Combined Positive Score (CPS) being >= 1 as per the Food and Drug
             Administration (FDA)-approved Dako PD-L1 immunohistochemistry (IHC) 22C3 PharmDx
             assay.

          -  Eastern Cooperative Oncology Group (ECOG) 0‐1.

          -  Body weight must be > 30 Kg.

          -  Hemoglobin > 8 g/dL.

          -  Absolute neutrophil count (ANC) > 1,200 x 10^9/mL.

          -  Platelet count > 75 x 10^9/mL.

          -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) OR direct bilirubin
             =< ULN if total bilirubin levels > 1.5 x ULN.

          -  Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT/serum glutamate-pyruvate transaminase [SGPT]) =< 5 x
             ULN.

          -  Prothrombin time (PT) and partial thromboplastin time (PTT) < 1.5 x the ULN.

          -  Serum creatinine =< 1.5 x ULN OR measured creatinine clearance (CL) > 40 mL/min or
             calculated creatinine clearance CL > 40 mL/min by the Cockcroft‐Gault formula or by
             24‐ hour urine collection for determination of creatinine clearance.

          -  Palliative radiation therapy is allowed to non‐target lesions at the discretion of the
             treating physician.

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) or
             evaluable disease as outlined in Response Evaluation Criteria in Solid Tumors (RECIST)
             version 1.1.

          -  Life expectancy of greater than 3 months in the opinion of the treating physician.

          -  Female patients of childbearing potential must have a negative serum pregnancy test
             within 7 days prior to enrollment.

        Exclusion Criteria:

          -  Prior exposure to the IRX‐2 regimen and/or PD‐1/PD‐L1 inhibitors are excluded.

          -  Radiation therapy with a curable intent within 30 days of first dose of study
             treatment is excluded. However, radiation therapy with a palliative intent is allowed
             as long as treatment with study medication occurs >= 14 days after the last dose of
             radiation.

          -  Any medical contraindications or previous therapy that would preclude treatment with
             the IRX‐2 regimen or pembrolizumab.

          -  Known allergies to ciprofloxacin or phytohemagglutin given trace amount of these
             agents are contained in IRX‐2.

          -  Patients with ongoing chronic myelosuppression, myelodysplasia, or hemorrhagic
             cystitis which would contraindicate receipt of cyclophosphamide.

          -  Any unresolved toxicity National Cancer Institute Common Terminology Criteria for
             Adverse Events (NCI CTCAE) grade >= 2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria.

          -  Patients with grade >= 2 neuropathy will be evaluated on a case‐by‐case basis after
             consultation with the study physician.

          -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with IRX‐2, pembrolizumab may be included only after consultation with the
             study physician.

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia.

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement.

               -  Any chronic skin condition that does not require systemic therapy.

               -  Patients without active disease in the last 2 years may be included but only
                  after consultation with the study physician.

               -  Patients with celiac disease controlled by diet alone.

          -  Current or prior use of immunosuppressive medication within 14 days prior to cycle 1,
             day 1. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroid or local steroid injections (e.g., intra
                  articular injection).

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent.

               -  Steroids as premedication for hypersensitivity reactions (e.g., computed
                  tomography [CT] scan premedication).

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to
             cycle 1, day 1. Note: Local surgery of isolated lesions for palliative intent is
             acceptable.

          -  History of allogeneic organ transplantation.

          -  Symptomatic cardiopulmonary disease (including congestive heart failure and
             hypertension), coronary artery disease, serious arrhythmia or chronic lung disease.
             Patients with these conditions who are stable with relatively minor symptoms and who
             are appropriate candidates for systemic treatments need not be excluded.

          -  Myocardial infarction within the last 3 months.

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

          -  Has a history of active hepatitis B requiring ongoing antiviral therapy or a history
             of untreated hepatitis C.

          -  Has received a live vaccine within 4 months of planned start of study therapy (cycle
             1, day 1).

               -  Note: The killed virus vaccines used for seasonal influenza vaccines for
                  injection are allowed provided not within 4 weeks of planned start of study
                  therapy (cycle 1, day 1); however intranasal influenza vaccines (e.g., FluMist)
                  are live attenuated vaccines and are not allowed.

          -  Signs or symptoms of systemic infection (use of antibiotics to treat superficial
             infection or contamination of tumor shall not, by itself, be considered evidence of
             infection).

          -  Stroke or other symptoms of cerebral vascular insufficiency within the last 3 months.

          -  Previous diagnosis of invasive cancer from which the individual is not disease‐free
             AND that has required treatment within the past 3 years, except for superficial skin,
             cervical cancer in‐situ, or early stage prostate or bladder cancer (i.e. treatment
             with curative intent and long term disease‐free expectations).

          -  History of leptomeningeal carcinomatosis.

          -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to one year after last dose of cyclophosphamide or 180 days after the last
             dose of pembrolizumab therapy, whichever is longer.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events as assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression-free survival assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and immune related (ir)RECIST
Time Frame:From first day of study drug administration to disease progression or death, assessed up to 2 years
Safety Issue:
Description:Kaplan‐Meier estimates and corresponding 95% confidence intervals for the median and quartiles will be provided.
Measure:Overall survival assessed by RECIST 1.1 criteria and irRECIST
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Overall response rate assessed by RECIST 1.1 criteria and irRECIST
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

January 8, 2020