PEN-221 in Somatostatin Receptor 2 Expressing Advanced Cancers Including Neuroendocrine and Small Cell Lung Cancers

Protocol PEN-221-001 will first enroll patients into a dose escalation phase, where a
Bayesian logistic regression model, guided by the escalation with overdose control principle
and overseen by a safety review committee, will be used to make dose recommendations and
estimate the maximum tolerated dose (MTD).

Once the MTD has been confirmed, remaining patients will be enrolled into a full expansion
phase to assess PEN-221 efficacy in patients with gastrointestinal mid-gut neuroendocrine
tumors or pancreatic neuroendocrine tumors or small cell lung cancer.

Inclusion Criteria:

- M/F at least 18 years old

- ECOG performance status 0 or 1

- Adequate bone marrow, liver, and kidney function within 2 weeks prior to first dose

- Serum potassium, calcium, magnesium, phosphorus within normal limits (may be
supplemented)

- Adequate birth control

- Somatostatin receptor 2 positive tumor as assessed at pre-screening or within 180 d of
first drug dose using indium SPECT or gallium PET

Patients in Phase 1 must have a histologically or cytologically-confirmed solid tumor in 1
of the following categories:

- Advanced small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC)
of lung progressed after at least 1 line of anticancer chemotherapy

- Advanced low or intermediate grade gastroenteropancreatic or lung or thymus
neuroendocrine tumor (NET), or NET of unknown primary, progressed after at least 1
line of anticancer therapy (unless no standard treatments available or such treatments
are deemed not appropriate)

- Advanced paraganglioma, pheochromocytoma, medullary thyroid carcinoma, Merkel cell
carcinoma, or high grade extrapulmonary neuroendocrine carcinoma having progressed
after 1 or more lines of anticancer chemotherapy (unless no standard treatments
available or such treatments are deemed not appropriate)

For patients enrolling once escalation is complete (Phase 2a), disease must be measurable
per RECIST 1.1 criteria with last imaging performed within 28 days prior to first drug dose

In addition to the criterion listed above, Patients in Phase 2a must have a histologically-
or cytologically-confirmed, advanced or metastatic solid tumor, in 1 of the following
categories: disease history specified in one of the criteria listed below:

- Well differentiated, low or intermediate grade, gastrointestinal mid-gut (arising from
the lower jejunum, ileum, appendix, cecum, and proximal colon) NET with documented
disease progression within 6 months prior to start of study treatment and evidence of
radiographic disease progression based on scans performed not more than 15 months
apart. Patients may have received 1 or more prior lines of anticancer therapy, such as
somatostatin analogues, targeted agents, or liver-directed intra-arterial therapy, but
are NOT eligible if they have received prior systemic cytotoxic chemotherapy.

- Well differentiated, low or intermediate grade, pancreatic NET with documented disease
progression within 6 months prior to start of study treatment and evidence of
radiographic disease progression based on scans performed not more than 15 months
apart. Patients may have received 1 or more prior lines of anticancer therapy, such as
somatostatin analogues, targeted agents, or liver-directed intra-arterial therapy, and
up to 1 prior line of systemic cytotoxic chemotherapy, but are NOT eligible if they
have received more than 1 prior line of systemic cytotoxic chemotherapy or if they
have received prior peptide receptor radionuclide therapy (PRRT)

- SCLC after having received up to three prior lines of anticancer therapy.

Exclusion Criteria:

- Treatment with anticancer therapy or investigational drug or device within 3 wk (6 wk
for nitrosureas or mitomycin C) or 5 half-lives of agent, whichever is shorter, prior
to first PEN-221 drug dose, and any drug-related toxicities must have recovered to
grade 1 or less

- Any other malignancy known to be active or treated within 3 years of start of
screening, except cervical intra-epithelial neoplasia, superficial (non-invasive)
bladder cancer, and non-melanoma skin cancer

- Cardiac criteria 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 1

- Requirement for medication with strong CYP3A4 inhibitor

- History of leptomeningeal disease or spinal cord compression

- Brain metastases unless asymptomatic on a stable low dose of steroids. Patients with
SCLC or LCNEC of lung only must have CT or MRI of brain during screening, and if
metastases found, must have radiotherapy with 14 day washout or stereotactic
radiotherapy or radio surgery with 7 day washout prior to first drug dose.

- Major surgery within 28 days of first drug dose

- Female who is pregnant or breast feeding

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

- Hypersensitivity or anaphylactic reaction to any somatostatin analog or to
maytansinoids