VX-970 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
VX-970 in combination with irinotecan hydrochloride (irinotecan) in patients with advanced
solid tumors.

SECONDARY OBJECTIVES:

I. To estimate the safety and tolerability of VX-970 in combination with irinotecan.

II. To document anti-tumor activity. III. To determine the pharmacokinetic (PK) and
pharmacodynamic (PD) parameters of VX-970 and irinotecan.

TERTIARY OBJECTIVES:

I. To identify molecular subpopulations of patients with increased sensitivity to the
irinotecan and VX-970 combination.

OUTLINE: This is a dose-escalation study.

Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and ATR kinase
inhibitor M6620 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, then at 3 and 6
months.

Inclusion Criteria:

- Patients must have histologically confirmed metastatic or unresectable malignancy that
is refractory to standard therapy or for which no standard therapy exists and where
irinotecan is deemed a reasonable treatment option

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- No limit on prior lines of therapy for metastatic disease; prior adjuvant or
neoadjuvant chemotherapy does not count as a prior line of therapy as long as
completion of the adjuvant or neoadjuvant therapy was more than 1 year prior to
patient enrollment

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal (ULN); if liver involvement, =< 5 x ULN

- Creatinine clearance >= 60 mL/min/1.73 m^2

- Patients must have archived tumor tissue from prior tumor biopsy or surgical
resections available for submission that is sufficient to complete molecular profiling

- FOR PATIENTS ENROLLED IN THE EXPANSION COHORT: willingness to undergo mandatory
biopsies (day -14, approximately 4 hours post end of irinotecan infusion and day 1,
approximately 4 hours post end of irinotecan infusion [= 3 hours post end of VX-970]);
patients enrolled to this cohort should have tumors deemed easily accessible for
biopsies with low likelihood of complication

- 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 and for
the duration of study participation; 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; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 6 months after completion of VX-970 administration; 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, for the duration of
study participation and for 6 months after study completion

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or other systemic therapy or radiotherapy or
patients who have not recovered from adverse events due to prior administered agents
as follows:

- Chemotherapy < 4 weeks prior to entering the study

- Radiotherapy < 4 weeks prior to entering the study

- Nitrosoureas/mitomycin C < 6 weeks prior to entering the study

- Targeted therapy < 2 weeks (or 5 half-lives, whichever is longer) prior to
entering the study

- Those who have not recovered from clinically significant adverse events due to
prior agents administered to grade =< 1 or baseline, with exception of alopecia
and peripheral neuropathy, unless approved by the protocol chair

- Patients who are receiving any other investigational agents

- Patients with unstable brain metastases should be excluded; however, patients with
known brain metastases may participate in this clinical trial if they are clinically
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 on a stable
or decreasing dose of steroids for at least 14 days prior to trial treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to VX-970 or irinotecan

- Concomitant administration with strong inhibitors or inducers of CYP3A4 should be
avoided; medications that enhance glucuronidation (i.e. phenytoin, phenobarbital,
carbamazepine, rifampin, etc.) should be avoided; it is important to regularly consult
a frequently-updated medical reference for a list of drugs to avoid or minimize use
of; as part of the enrollment/informed consent procedures, the patient will be
counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product

- Uncontrolled intercurrent illness including, but not limited to, severe active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements; patients with chronic viral hepatitis may participate in this
clinical trial if they are clinically stable with acceptable liver function

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with VX-970

- Human immunodeficiency virus (HIV)-positive patients with well-controlled disease, as
determined by CD4 count and viral load, who are on antiretroviral therapy that does
not contain a strong inducer or inhibitor of CYP3A4 (e.g. regimens containing
ritonavir, cobicistat, efavirenz or etravirine) are allowed on trial; HIV-positive
patients on combination antiretroviral therapy with strong inducers or inhibitors of
CYP3A4 are ineligible; patients with poorly controlled HIV are not eligible