An Exploratory Study of the Folic Acid-tubulysin Conjugate EC1456 in Ovarian Cancer Subjects Undergoing Surgery

Study EC1456-02 is an exploratory, open-label study that seeks to enroll subjects with
ovarian cancer who will be undergoing therapeutic debulking surgery.

All subjects will undergo a 99mTc-etarfolatide scan within 2 weeks prior to EC1456
administration. Briefly, prior to the 99mTc-etarfolatide imaging procedure, all subjects will
receive one intravenous (IV) injection of folic acid or unlabeled etarfolatide, followed
within 1 to 3 minutes by an injection of 99m Tc-etarfolatide (i.e., etarfolatide labeled with
740 to 925 megabecquerels (MBq) [20 to 25 millicuries (mCi)] of sodium pertechnetate Tc-99m
injection).

Individual subjects will receive 1 of the following 2 doses of EC1456 pre-operatively:

- 4 milligrams (mg)/meter (m)2

- 8 milligrams (mg)/meter (m)2

EC1456 will be administered at 1 of the following 2 time points:

- <8 hours before planned surgery

- 48±4 hours before planned surgery

The 4 mg/m2 dose of EC1456 administered <8 hours prior to surgery will be the first dose
cohort to enroll. Once enrollment to this cohort is complete, the remaining cohorts will be
open for enrollment. Assignment to specific cohorts will be determined by the Sponsor based
on data assessed from previously enrolled subjects. Two to six subjects will be enrolled per
cohort as shown below.

- Cohort 1: 4 mg/m2 EC1456 <8 hours prior to surgery

- Cohort 2: 4 mg/m2 EC1456 48±4 hours prior to surgery

- Cohort 3: 8 mg/m2 EC1456 <8 hours prior to surgery

- Cohort 4: 8 mg/m2 EC1456 48±4 hours prior to surgery

In the event of unexpected results, lower, intermediate or higher EC1456 levels up to 12.5
mg/m2, the highest determined safe dose of EC1456 as defined by the parallel phase I study
EC1456-01, may be explored.

The first on-study procedure will be SPECT or SPECT/CT with 99mTc-etarfolatide. SPECT or
SPECT/CT scans will be acquired within 2 weeks prior to EC1456 administration as specified in
the Imaging Operations Manual.

EC1456 will be administered pre-operatively as an intravenous (IV) bolus infusion at 1 of 2
time points:

1. < 8 hours preceding surgery or

2. 48±4 hours preceding surgery.

At 2 time points:

1. within approximately 15 (±5) minutes post-EC1456 administration and

2. at the start of surgery, approximately 5 mL of whole blood will be drawn for EC1456
analyses.

Tissues to be collected at surgery, if present, include: sample of 1 or both ovaries,
endometrium, omentum, ascitic fluid and/or selected lesions as identified by the surgeon or
sponsor. The location of each sample will be annotated such that the ex vivo analysis may be
correlated with the SPECT/CT image post-surgery. Samples of tumor tissue will be collected at
the time of surgery, aliquoted into collection vials, and placed on dry ice or in buffered
formalin.

Inclusion Criteria:

1. Subject must have the ability to understand, and have signed an approved informed
consent form (ICF).

2. Subjects must have cytologically or pathologically confirmed advanced ovarian cancer
and be scheduled for primary, interval, or secondary, cytoreductive surgery as a part
of standard of care for treatment of ovarian cancer, and have at least 1 lesion that
can be removed at surgery.

3. Subject must be ≥18 years of age.

4. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1.

5. Subjects with central nervous system (CNS) metastases must be neurologically stable
and off of steroids for at least 14 days before pre-registration. Subjects with
asymptomatic CNS metastatic disease without associated edema, shift, and a requirement
for steroids or anti-seizure medications may be eligible after discussion with the
sponsor's medical monitor.

6. Subjects must have recovered (to baseline/ stabilization) from prior chemo- or
radiotherapy and associated acute toxicities must have resolved to a NCI CTCAE v4
Grade 1 or less, with the exception of alopecia.

7. Subject must have adequate organ function:

- Bone marrow reserve:

- Absolute neutrophil count ≥1.5 × 109/L.

- Platelets ≥100 × 109/L.

- Hemoglobin ≥9 g/dL.

- Cardiac:

- Left ventricular ejection fraction (LVEF) ≥ the institutional lower limit of
normal. LVEF must be evaluated within 28 days prior to the dose of EC1456.

- Cardiac Troponin I within normal limits.

- Electrocardiogram QT segment corrected by the method of Fridericia
QTcFridericia (QTcF) < 450 msec on at least 2 of 3 screening ECG's. On site
determination of QTcF may be used for screening purposes.

- Hepatic:

- Total bilirubin ≤1.5 × the upper limit of normal (ULN).

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST

- 3.0 × ULN, or ≤5.0 × ULN for subjects with liver metastases.

- Renal: Serum creatinine ≤1.5 × ULN, or for subjects with serum creatinine
>1.5 × ULN, creatinine clearance ≥50 mL/min.

8. Subjects of childbearing potential:

- All women of childbearing potential MUST have a negative urine or serum pregnancy
test within 1 week prior to the 99mTc-etarfolatide imaging procedure and within 1
week prior to the dose of EC1456.

- Women of childbearing potential must practice an effective method of birth
control (e.g., oral, transdermal or injectable contraceptives, intrauterine
device [IUD], or double-barrier contraception, such as diaphragm and spermicidal
jelly) for the duration of their participation in

Exclusion Criteria:

1. In the opinion of the investigator, a subject's physical condition might create a
hardship for tolerating the radionuclide imaging procedures or a single administration
of EC1456 (e.g., due to pain or dyspnea in prolonged supine positions).

2. Use of the following medications within 6 months prior to EC1456 administration:
amiodarone, disopyramide, dofetilide, dronedarone, flecanamide, ibutilide, quinidine,
or sotalol.

3. Subject has a co-morbid medical condition that, in the opinion of the investigator, is
known to have a major impact on the pharmacokinetics (PK), distribution, metabolism,
or elimination of either small molecule drug conjugate (SMDC).

4. Subject has known active hepatitis B or hepatitis C.

5. Subject has active uncontrolled infection(s).