Clinical Trials /

Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer

NCT03095781

Description:

This phase Ib trial studies the side effects and best dose of Hsp90 inhibitor XL888 when given together with pembrolizumab in treating patients with advanced gastrointestinal cancer that has spread to other places in the body. XL888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving XL888 with pembrolizumab may work better in treating patients with gastrointestinal cancer.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Cholangiocarcinoma
  • Colorectal Adenocarcinoma
  • Gastric Adenocarcinoma
  • Hepatocellular Carcinoma
  • Pancreatic Adenocarcinoma
  • Small Intestinal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer
  • Official Title: Phase Ib Trial of Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Malignancies

Clinical Trial IDs

  • ORG STUDY ID: IRB00087397
  • SECONDARY ID: NCI-2016-01594
  • SECONDARY ID: Winship3321-16
  • NCT ID: NCT03095781

Conditions

  • Adenocarcinoma of the Gastroesophageal Junction
  • Colorectal Adenocarcinoma
  • Metastatic Pancreatic Adenocarcinoma
  • Non-Resectable Cholangiocarcinoma
  • Non-Resectable Hepatocellular Carcinoma
  • Recurrent Cholangiocarcinoma
  • Recurrent Colorectal Carcinoma
  • Recurrent Gastric Carcinoma
  • Recurrent Hepatocellular Carcinoma
  • Recurrent Pancreatic Carcinoma
  • Recurrent Small Intestinal Carcinoma
  • Small Intestinal Adenocarcinoma
  • Stage III Colorectal Cancer
  • Stage III Gastric Cancer
  • Stage III Hepatocellular Carcinoma
  • Stage III Pancreatic Cancer
  • Stage III Small Intestinal Cancer
  • Stage IIIA Colorectal Cancer
  • Stage IIIA Gastric Cancer
  • Stage IIIA Hepatocellular Carcinoma
  • Stage IIIA Small Intestinal Cancer
  • Stage IIIB Colorectal Cancer
  • Stage IIIB Gastric Cancer
  • Stage IIIB Hepatocellular Carcinoma
  • Stage IIIB Small Intestinal Cancer
  • Stage IIIC Gastric Cancer
  • Stage IV Colorectal Cancer
  • Stage IV Gastric Cancer
  • Stage IV Hepatocellular Carcinoma
  • Stage IV Pancreatic Cancer
  • Stage IV Small Intestinal Cancer
  • Stage IVA Colorectal Cancer
  • Stage IVA Hepatocellular Carcinoma
  • Stage IVA Pancreatic Cancer
  • Stage IVB Colorectal Cancer
  • Stage IVB Hepatocellular Carcinoma
  • Stage IVB Pancreatic Cancer
  • Unresectable Pancreatic Carcinoma
  • Unresectable Small Intestinal Carcinoma

Interventions

DrugSynonymsArms
XL888Heat Shock Protein 90 Inhibitor XL888, Hsp90 Inhibitor XL888Treatment (pembrolizumab, XL888)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, XL888)

Purpose

This phase Ib trial studies the side effects and best dose of Hsp90 inhibitor XL888 when given together with pembrolizumab in treating patients with advanced gastrointestinal cancer that has spread to other places in the body. XL888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving XL888 with pembrolizumab may work better in treating patients with gastrointestinal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the recommended phase II dose for the combination of XL888 and pembrolizumab.

      SECONDARY OBJECTIVES:

      I. Define the toxicity profile of the combination of XL888 and pembrolizumab.

      II. Evaluate the activity of the combination of XL888 and pembrolizumab in previously
      treated patients with gastrointestinal tumors.

      TERTIARY OBJECTIVES:

      I. Evaluate the effect of the combination on the immune profile in the serum and in tumor
      biopsies.

      OUTLINE: This is a dose-escalation study of Hsp90 inhibitor XL888.

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and XL888 orally
      (PO) on day 1, 4, 8, 11, 15, and 18. Courses repeat every 21 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and periodically
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, XL888)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and XL888 PO on days 1, 4, 8, 11, 15, and 18. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • XL888

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with stage IV or locally advanced unresectable gastrointestinal
             adenocarcinomas (gastric, gastroesophageal junction [GEJ], cholangiocarcinoma,
             hepatocellular, pancreas, colorectal, small intestinal tumors) who have failed at
             least one prior therapy (dose escalation phase)

          -  Patients with pancreatic adenocarcinoma; patients must have histologic diagnosis and
             either locally advanced unresectable or metastatic disease that has failed at least
             one standard regimen; eight patients must have tumors that are accessible for biopsy
             and sign the informed consent for paired biopsy study (dose escalation phase, arm A)

          -  Patients with colorectal adenocarcinoma; patients must have histologic diagnosis and
             either locally advanced unresectable or metastatic disease and have previously
             received oxaliplatin, irinotecan, and fluoropyrimidine; eight patients must have
             tumors that are accessible for biopsy and sign the informed consent for paired biopsy
             study (dose escalation phase, arm B)

          -  Be willing and able to provide written informed consent/assent for the trial

          -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Absolute neutrophil count (ANC) ≥ 1,500 cells/µL

          -  Platelets ≥ 100,000 cells/µL

          -  Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment)

          -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl]) ≥ 60 mL/min for subject with creatinine
             levels > 1.5 x institutional ULN

               -  Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x
             ULN OR ≤ 5 x ULN for subjects with liver metastases

          -  Albumin ≥ 2.5 mg/dL

          -  International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended
             use of anticoagulants

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication; if
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception, starting with the first dose of study therapy through 120 days after
             the last dose of study therapy.

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the subject

          -  Female subjects of childbearing potential must be willing to use an adequate method
             of contraception for the course of the study through 120 days after the last dose of
             study medication

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the subject

        Exclusion Criteria:

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of
             trial treatment

          -  Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)

          -  Hypersensitivity to pembrolizumab or history of severe allergic or hypersensitivity
             reactions to excipients (e.g., polyethylene glycol [PEG] 300 and polysorbate 80)

          -  Clinically significant cardiovascular disease or peripheral vascular (e.g. myocardial
             infarction, unstable angina within 6 months of study entry), symptomatic congestive
             heart failure, serious uncontrolled cardiac arrhythmia requiring medications,
             baseline corrected QT (QTc) > 450 msec or previous history of QT prolongation while
             taking other medications

          -  Other medications, or severe acute/chronic medical or psychiatric condition, or
             laboratory abnormality that may increase the risk associated with study participation
             or study drug administration, or may interfere with the interpretation of study
             results, and in the judgment of the investigator would make the subject inappropriate
             for entry into this study

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at
             baseline) from adverse events due to a previously administered agent

               -  Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

               -  Note: If subject received major surgery, they must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  therapy

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis; subjects with previously treated brain metastases may participate
             provided they are stable (without evidence of progression by imaging for at least
             four weeks prior to the first dose of trial treatment and any neurologic symptoms
             have returned to baseline), have no evidence of new or enlarging brain metastases,
             and are not using steroids for at least 7 days prior to trial treatment; this
             exception does not include carcinomatous meningitis which is excluded regardless of
             clinical stability

          -  Has active autoimmune disease that has required systemic treatment in the past 2
             years (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary
             insufficiency, etc.) is not considered a form of systemic treatment

          -  Has known history of, or any evidence of active, non-infectious pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has known substance abuse disorders that would interfere with cooperation with the
             requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or
             anti-PD-L2 agent

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

          -  Has known active hepatitis B (e.g., hepatitis surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has received a live vaccine within 30 days of planned start of study therapy

               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
                  are live attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose of the combination of XL888 and pembrolizumab as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Cycle length 21 days. Outcome determined on day 22 (after completion of cycle 1)
Safety Issue:
Description:Summary statistics will be presented. Toxicities will be presented as worst toxicity per patient and will be reported as percent toxicity.

Secondary Outcome Measures

Measure:Overall response rate as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame:Up to 2 years after cycle 1, day 1. Cycle length is 21 days.
Safety Issue:
Description:RECIST version 1.1 will be used in this study for assessment of tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.
Measure:Overall survival
Time Frame:Up to 1 year after cycle 1, day 1. Each cycle is 21 days.
Safety Issue:
Description:Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the survival follow-up phase and should be contacted by telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first.
Measure:Progression free survival
Time Frame:Up to 6 months after cycle 1, day 1. Each cycle is 21 days
Safety Issue:
Description:Summary statistics will be presented.
Measure:Response duration as assessed by RECIST 1.1
Time Frame:Up to 2 years after cycle 1, day 1. Each cycle is 21 days.
Safety Issue:
Description:Summary statistics will be presented.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Last Updated

March 28, 2017