Pembrolizumab And XL888 In Patients With Advanced Gastrointestinal Cancer

Study Overview

Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer

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.

PRIMARY OBJECTIVE: 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 OBJECTIVE: 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.

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

DRUG: XL888
BIOLOGICAL: Pembrolizumab

IRB00087397
NCI-2016-01594 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
Winship3321-16 (OTHER Identifier) (OTHER: Emory University/Winship Cancer Institute)
P30CA138292 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2017-03-22	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-11-29
First Submitted that Met QC Criteria 2017-03-28	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-12-05
First Posted (ACTUAL) 2017-03-30	Results First Posted N/A	Last Verified 2023-11

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (pembrolizumab, XL888) 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 Given PO BIOLOGICAL: Pembrolizumab Given IV

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (pembrolizumab, XL888)

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

Given PO

BIOLOGICAL: Pembrolizumab

Given IV

Primary Outcome Measures	Measure Description	Time Frame
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 Outcome Measures	Measure Description	Time Frame
Overall response rate as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1	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.	Up to 2 years after cycle 1, day 1. Cycle length is 21 days.
Overall survival	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.	Up to 1 year after cycle 1, day 1. Each cycle is 21 days.
Progression free survival	Summary statistics will be presented.	Up to 6 months after cycle 1, day 1. Each cycle is 21 days
Response duration as assessed by RECIST 1.1	Summary statistics will be presented.	Up to 2 years after cycle 1, day 1. Each cycle is 21 days.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Merck Sharp & Dohme LLC
Exelixis
National Institutes of Health (NIH)
National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Maria Diab, MD, Emory University/Winship Cancer Institute

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

No publications available

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