PEN-866 in Patients With Advanced Solid Malignancies

Phase 1 will employ an adaptive model guided with overdose control principle to make dose
recommendations and estimate the maximum tolerated dose (MTD).

Phase 2a begins once all patients treated in Phase 1 have been assessed for safety and the
Safety Review Committee (SRC) has reviewed all safety data and recommends continuing with
Phase 2a. PEN-866 will be evaluated using the recommended Phase 2 dose identified by the SRC
at the conclusion of Phase 1 based on the safety, tolerability, pharmacokinetic, and
pharmacodynamics profile of PEN-866 during Phase 1.

Inclusion Criteria:

- M/F at least 18 years old

- Performance status 0 or 1

- Adequate bone marrow, liver, and kidney function within 28 days prior to first dose

- Serum potassium, calcium, magnesium, phosphorus within normal limits

- Adequate birth control

- Central venous access line is required

- Patients in Phase 1 must also have confirmed advanced solid malignancy that has
progressed after one or more prior lines of anticancer therapy and no other standard
of care therapies that are deemed appropriate for treatment of their malignancy

- Patients in Phase 2a must have confirmed diagnosis and specific disease history of
Ewing sarcoma, or rhabdomyosarcoma, or small-cell lung cancer, or triple-negative
breast cancer, or pancreatic adenocarcinoma, or colorectal cancer, or gastric
adenocarcinoma

- Patients in Phase 2a must have measurable disease per RECIST 1.1 and documented
disease progression during or after their most recent line of anticancer therapy.

Exclusion Criteria:

- Treatment with anticancer therapy or investigational drug or device within 2 wk (6 wk
for nitrosureas or mitomycin C) or 5 half-lives of agent, whichever is shorter, prior
to first drug dose, and any drug-related toxicities must have recovered to grade 1 or
less

- History within last 5 years of an invasive malignancy other than resected/ablated
basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or
other local tumors considered cured by local treatment

- Cardiac disease such as unstable angina, myocardial infarction within 6 months of
screening, NY Heart Association Class 1 or 2 heart failure, QTc greater than 470 msec,
congenital long Qt syndrome, symptomatic orthostatic hypotension within 6 months of
screening, uncontrolled hypertension, or clinically important abnormalities in heart
rhythm, conduction, morphology of resting ECG

- Stroke or transient ischemic attack within 6 months of screening

- Peripheral neuropathy greater than grade 2

- Patients requiring medications with drugs that are inhibitors of UGT1A1 or substrates
of CYP1A2, P-gP, BCRP, OATP1B1, OATP1B3 or OCT1 transporters

- History of leptomeningeal disease or spinal cord compression

- Brain metastases unless asymptomatic and not requiring steroids for at least 4 weeks
prior to start of study treatment

- Major surgery within 28 days of first drug dose

- Female pregnant or breast feeding

- Evidence of severe uncontrolled systemic disease, bleeding diatheses, renal or liver
transplant, active infection with hep B or C or HIV

- Hypersensitivity or anaphylactic reaction to ganetespib or other HSP90 inhibitors,
irinotecan, SN-38 or its derivatives

- Patients in Phase 1 must not have a genotype of UGT1A1 1*28/*28