Trial of Topotecan With VX-970, an ATR Kinase Inhibitor, in Small Cell Cancers Amd Extrapulmonary Small Cell Cancers

Background:

Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.

Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and
becomes refractory to treatment within a few months.

There is only one FDA approved treatment for patients with relapsed SCLC after first-line
chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand
DNA breaks leading to lethal doublestrand DNA breaks.

The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests
the existence of a highly effective DNA damage response network.

SCLC is characterized by high replication stress (RB1 inactivation, MYC and CCNE1 activation)
and defective ATM-p53 signaling pathway, which cause an excessive reliance on ATR for
survival following DNA damage.

We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as
topotecan will provide an attractive synthetically lethal therapeutic option for SCLC.

VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the
hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents.

Primary objectives:

Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with
VX-970.

Phase 2: To assess the efficacy with respect to clinical response rate of a combination of
topotecan and VX-970 in the second-line treatment of patients with SCLC.

Eligibility:

Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a
performance status (ECOG) less than or equal to 2. Subjects must not have received
chemotherapy, or undergone major surgery within 4 weeks and radiotherapy within 24 hours
prior to enrollment.

Phase 1: Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical cancer,
and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other
histolgies will be allowed if no standard treatment options exist. Patients with evaluable,
but not measurable disease will be eligible for Phase I.

Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based
chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be
eligible. Patients must have measurable disease to be eligible for Phase II.

Design:

Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970
administered every 21 days (1 cycle), until disease progression or development of intolerable
side effects.

Blood and hair samples will be collected at multiple time points during cycle 1
(pre-treatment on day 1, post treatment on days 2, and 3) for PD analyses.

Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment
cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease
progression except for subjects at the first dose level.

Participants at the first dose level will undergo biopsies on day 3 prior to third dose of
topotecan.

Participants will be monitored weekly during the first cycle by clinic visit and basic labs.

Toxicity will be graded according to CTCAE version 4.0, and tumor assessments will be made
using CT scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to
Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1.

Follow-up for survival will be carried out every 3 months.

- INCLUSION CRITERIA:

- Both Phase I and Phase II:

- Male and female subjects greater than or equal to 18 years of age. Because no
dosing adverse event data are currently available on the use of topotecan in
combination with VX-970 in subjects less than 18 years of age, children are
excluded from this study, but will be eligible for future pediatrics trials.

- ECOG performance status less than or equal to 2 (Performance Status Criteria)

- Patients must have measurable disease, per RECIST 1.1. Subjects with evaluable,
but not measurable disease will be eligible for Phase 1.

- Subjects must not have received chemotherapy, or undergone major surgery within 4
weeks and radiotherapy within 24 hours prior to enrollment.

- Adequate organ functions

- Hemoglobin greater than or equal to 9.0 g/dL

- Absolute neutrophil count greater than or equal to 1.5x10^9/L

- Platelets greater than or equal to 100x10^9/L

- Total Bilirubin less than or equal to 2.0 mg/dL

- Transaminases less than or equal to 2 x ULN or if liver metastases were
present, less than or equal to 3xULN

- Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by
Cockcroft-Gault formula greater than or equal to 60 mL/min

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- The effects of VX-970 on the developing human fetus are unknown For this reason
and because topotecan is known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry, during study
participation and for 6

months after the last dose study therapy. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform her
treating physician immediately.

- Phase I:

- Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical
cancer, and neuroendocrine cancers will be eligible. Pathological confirmation of
diagnosis will be done at NCI Laboratory of Pathology. Patients with other
histologies will be allowed if no standard treatment options exist.

- At least one prior chemotherapy

- NSCLC subjects with EGFR mutations or ALK translocations should have previously
received appropriate FDA approved therapies in addition to prior chemotherapy

- Phase II:

- Histological confirmation of SCLC, or extrapulmonary small cell cancer. Although
NCI confirmation of pathology is not required prior to starting treatment, every
effort will be made to obtain outside pathology to be reviewed by an NCI
pathologist.

- Subjects with both platinum-sensitive and platinum-refractory disease will be
eligible

EXCLUSION CRITERIA:

- Subjects with tumor amenable to potentially curative therapy.

- Subjects who are receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to (study agent) or other agents used in study.

- Subjects with symptomatic brain metastases will be excluded from trial secondary to
poor prognosis. However, subjects who have had treatment for their brain metastasis
and whose brain disease is stable without steroid therapy for 1 week or on physiologic
doses of steroids may be enrolled.

- Subjects requiring any medications or substances that are strong inhibitors or
inducers of CYP3A during the course of the study are ineligible. Lists including
strong inhibitors and inducers of CYP 3A4 are provided.

- Subjects with evidence of severe or uncontrolled systemic disease, or any concurrent
condition, which could compromise participation in the study, including, but not
limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B,
Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive
heart failure, unstable angina pectoris, myocardial infarction within the past 6
months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the
past 6 months, or psychiatric illness/social situations which would jeopardize
compliance with the protocol.

- HIV-positive subjects on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with VX-970. In addition, these
subjects are at increased risk of lethal infections when treated with
marrow-suppressive therapy.

- Pregnant women are excluded from this study because topotecan is a Class D agent with
the potential for teratogenic or abortifacient effects and because the effects of VX-
970 on the developing human fetus are currently unknown. In addition, because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with topotecan or VX-970, breastfeeding should be discontinued
if the mother is treated with these agents.