Liposomal Irinotecan and Veliparib in Treating Patients With Solid Tumors

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of escalating doses of liposomal irinotecan
(MM-398) + veliparib combination.

II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the
combination of MM-398 + veliparib.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To characterize the preliminary efficacy of
the combination using key efficacy indicators, such as objective response rate, clinical
benefit rate defined as complete response (CR), partial response (PR), or stable disease (SD)
at 24 weeks, and progression free survival (PFS).

EXPLORATORY OBJECTIVES I. Imaging, tumor, and blood biomarkers to assess the sensitivity or
resistance to each drug and/or correlation with clinical response.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive liposomal irinotecan intravenously (IV) over 90 minutes on days 1 and 15 and
veliparib orally (PO) twice daily (BID) on days 5-12 and 19-25 or 3-12 and 17-25. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity. Within
2-6 days prior to beginning liposomal irinotecan treatment, patients may optionally receive
ferumoxytol (FMX) IV and undergo magnetic resonance imaging (MRI) at baseline and 24 hours
after FMX infusion.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have pathologically confirmed diagnosis of a solid tumor cancer for
which there is no known standard therapy capable of extending life expectancy

- Prior poly ADP ribose polymerase (PARP) inhibitor therapy is allowed; patients with
ovarian cancer and a BRCA mutation should have had prior treatment with olaparib per
guidelines for standard of care treatment

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Hemoglobin > 9 g/dL

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL without the use of hematopoietic growth factors

- Platelets >= 100,000/mcL

- Total bilirubin below normal institutional upper limit of normal (ULN)

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

- Creatinine =< 1.5 x ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Women of childbearing potential and male patients should use effective contraception
during treatment with MM-398 and for 90 days following the final dose of veliparib and
MM-398 for both female and male patients; 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

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

- IMAGING CORRELATIVE STUDY: Patients will be eligible to participate in the FMX imaging
study if the participating study center offers this test and they do not meet any of
the following criteria:

- Evidence of iron overload as determined by:

- Fasting transferrin saturation of > 45% and/or

- Serum ferritin levels > 1000 ng/ml

- A history of allergic reactions to any of the following:

- Compounds similar to ferumoxytol or any of its components as described in
full prescribing information for ferumoxytol injection

- Any IV iron replacement product (e.g. parenteral iron, dextran,
iron-dextran, or parenteral iron polysaccharide preparations)

- Multiple drugs

- Unable to undergo MRI or for whom MRI is otherwise contraindicated (e.g. presence
of errant metal, cardiac pacemakers, pain pumps or other MRI incompatible
devices; or history claustrophobia or anxiety related to undergoing MRI)

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those whose adverse events
have not resolved to grade 1 or less (except alopecia) from agents administered more
than 4 weeks earlier; patients must have completed prior biological therapies and/or
targeted therapies >= 2 weeks prior to study enrollment; patients who have had
radiation to the pelvis or other bone marrow-bearing sites will be considered on a
case by case basis and may be excluded if the bone marrow reserve is not considered
adequate (i.e. radiation to > 25% of bone marrow)

- Patients who are receiving any other investigational agents

- 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 at least 3 months may be
enrolled

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to veliparib and MM-398; if patients have a history of allergic reactions
to compounds resembling MM-398, they will be excluded from participating in the FMX
MRI study, if applicable

- Patients who have severe hypersensitivity to irinotecan hydrochloride (HCl)

- Patients with known and confirmed diagnosis of interstitial lung disease (IDL)

- Clinically significant gastrointestinal (GI) disorders, including history of small
bowel obstruction unless the obstruction was a surgically treated remote episode

- Patient is unable to swallow or keep down oral medication

- Patients at the National Cancer Institute (NCI) site and other selected centers who
are willing to undergo an optional pre-treatment ferumoxytol MRI must not have
evidence of iron overload, a known hypersensitivity to ferumoxytol or any other IV
iron product, a documented history of multiple drug allergies, or those for whom MRI
is otherwise contraindicated, including claustrophobia or anxiety related to
undergoing MRI; this exclusion criterion applies only to patients enrolling at NCI and
other selected sites; of note, the principal investigator (PI) will allow other
centers to offer FMX MRI scans if the site in question is willing and the site PI can
identify the necessary resources and expertise at their center

- Active infection

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with any of these agents

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- Patients who need chronic use of medications or substances that are strong inhibitors
or inducers of CYP3A4 are ineligible

- Patients with a high risk of seizures should be excluded from the protocol (e.g. those
patients with an uncontrolled seizure disorder, and/or patients who have had a focal
or generalized seizure within the last 12 months)