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

A Phase 1b/2 Trial of the IRX-2 Regimen and Pembrolizumab in Patients With Advanced Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma

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.

Study Overview

• Status: Completed
• Conditions: Clinical Stage IV Gastric Cancer AJCC v8; Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8; Metastatic Gastric Adenocarcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; 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; Clinical Stage IVA Gastric Cancer AJCC v8; Clinical Stage IVB Gastric Cancer AJCC v8; Pathologic Stage IV Gastric Cancer AJCC v8; Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8; Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8; Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma 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; Recurrent Gastric Adenocarcinoma; Recurrent Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Cyclophosphamide; Biological: Cytokine-based Biologic Agent IRX-2

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth Research Institute
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology at Baylor Charles A Sammons Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (pembrolizumab, cyclophosphamide, and IRX-2); Participants 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.

Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Biological: Cytokine-based Biologic Agent IRX-2; Given SC; Other Names: IRX-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Estimated using the product-limit method of Kaplan and Meier. From initial treatment until progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	From first day of study drug administration to disease progression or death, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Estimated using the product-limit method of Kaplan and Meier. From the time of initial treatment until death from any cause.	Up to 2 years
Overall Response	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating T cell profiles for each participant with the combination of IRX-2 regimen and pembrolizumab	Will be compiled using descriptive statistics. Data will be screened for parametric statistical assumption and the alpha level for all statistical tests will be set at .05. The Bonferroni correction will be applied to adjust for potentially inflated family wise error rates for multiple comparisons with the same sample.	At pre- and post-intervention assessed up to 2 years
Difference in tumor tissue Nanostring expression profiling	Will conduct repeated measures t-tests. Data will be screened for parametric statistical assumption and the alpha level for all statistical tests will be set at .05. The Bonferroni correction will be applied to adjust for potentially inflated family wise error rates for multiple comparisons with the same sample.	From baseline to post-treatment assessed up to 2 years
Identification of tumor neoantigens using multiplex proteomic assay (MCH-PepSeq) assay		Up to 2 years
Hypothesis development for response based on circulating immune cell profiles circulating tumor deoxyribonucleic acid (DNA) from peripheral blood		Up to 2 years

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2019
• Primary Completion (Actual): February 9, 2023
• Study Completion (Actual): February 9, 2023

Study Registration Dates

• First Submitted: September 10, 2018
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (Actual): April 17, 2019

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 21, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Stomach Neoplasms; Recurrence; Adenocarcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Pembrolizumab
• Other Study ID Numbers: 18069 (Other Identifier: City of Hope Comprehensive Cancer Center); NCI-2018-01885 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• 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