Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer

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.

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