Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer

NCT03095781 | Completed Phase 1 DMC FDA Drug

• 4 other identifiers: IRB00087397NCI-2016-01594Winship3321-16P30CA138292
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Colorectal Adenocarcinoma; Metastatic Pancreatic Adenocarcinoma; Recurrent Colorectal Carcinoma; Recurrent Pancreatic Carcinoma; Stage III Colorectal Cancer; Stage III Pancreatic Cancer; Stage IIIA Colorectal Cancer; Stage IIIB Colorectal Cancer; Stage IV Colorectal Cancer; Stage IV Pancreatic Cancer; Stage IVA Colorectal Cancer; Stage IVA Pancreatic Cancer; Stage IVB Colorectal Cancer; Stage IVB Pancreatic Cancer; Unresectable Pancreatic Carcinoma

Outcome Measures

Primary Outcomes (1)

• 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

  Summary statistics will be presented. Toxicities will be presented as worst toxicity per patient and will be reported as percent toxicity.

  Cycle length 21 days. Outcome determined on day 22 (after completion of cycle 1)

Secondary Outcomes (4)

• Overall response rate as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

  Up to 2 years after cycle 1, day 1. Cycle length is 21 days.

• Overall survival

  Up to 1 year after cycle 1, day 1. Each cycle is 21 days.

• Progression free survival

  Up to 6 months after cycle 1, day 1. Each cycle is 21 days

• Response duration as assessed by RECIST 1.1

  Up to 2 years after cycle 1, day 1. Each cycle is 21 days.

Other Outcomes (1)

• Immune profile effects of pembrolizumab and Hsp90 inhibitor XL888 assessed in serum and tumor biopsies

  Up to 2 years after cycle 1, day 1. Each cycle is 21 days.

Study Arms (1)

Treatment (pembrolizumab, XL888)

EXPERIMENTAL

Patients 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.

Drug: XL888; Biological: Pembrolizumab

Interventions

XL888 DRUG

Given PO

Also known as: Heat Shock Protein 90 Inhibitor XL888, Hsp90 Inhibitor XL888

Treatment (pembrolizumab, XL888)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Treatment (pembrolizumab, XL888)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Emory University: lead
• Merck Sharp & Dohme LLC: collaborator
• Exelixis: collaborator
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (3)

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Pancreatic Neoplasms

Interventions

XL 888; pembrolizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Maria Diab, MD

  Emory University/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 22, 2017
• First Posted: March 30, 2017
• Study Start: July 7, 2017
• Primary Completion: June 10, 2021
• Study Completion: June 10, 2021
• Last Updated: December 5, 2023

Record last verified: 2023-11

Locations

US (3)