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Phase 1 Trial of ABT-888 and SCH727965 Without or With Carboplatin in Patients With Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
BRCA1 Mutation Carrier, BRCA2 Mutation Carrier, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase 1 Trial of ABT-888 and SCH727965 Without or With Carboplatin in Patients With Advanced Solid Tumors


PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of veliparib (ABT-888) and dinaciclib (SCH727965)
without or with carboplatin in patients with advanced solid tumors.

II. To determine the recommended phase 2 dose (RP2D) for ABT-888 in combination with
SCH727965 without or with carboplatin, determined by evaluating the feasibility, safety,
dose-limiting toxicities, and the maximally tolerated dose(s).

SECONDARY OBJECTIVES:

I. To confirm the safety of the combination of ABT-888 and SCH727965 without or with
carboplatin in patients with known BRCA1 or BRCA2 germline mutation.

II. To characterize the pharmacokinetic parameters of ABT-888 both alone and in combination
with SCH727965 without or with carboplatin.

III. To assess the pharmacodynamic effects of ABT-888 in combination with SCH727965 without
or with carboplatin, both in surrogate tissues and in tumor.

IV. To assess preliminary antitumor activity of the ABT-888/SCH727965 and
ABT-888/SCH727965/carboplatin combinations in subjects with solid tumors.

OUTLINE: This is a dose-escalation study of veliparib and dinaciclib followed by an expanded
BRCA-proficient and BRCA-deficient cohort study.

PART 1: Patients receive veliparib orally (PO) twice daily (BID) on days 1-28 and dinaciclib
IV over 2 hours on days 8 and 22. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity. Once the maximum-tolerated dose (MTD) is determined,
part 2 of study is initiated.

PART 2: Patients receive veliparib and dinaciclib as patients in part 1. Patients also
receive carboplatin IV over 60 minutes on days 8 and 22. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetic and pharmacodynamic studies, circulating tumor cells, and other correlative
studies. Patients also undergo skin biopsy at baseline and on day 8 for correlative studies.
Some patients undergo tumor biopsy (Tru-cut or core biopsy) on days 6 or 7 and 9 or 10 for
correlative studies. Archived tumor tissue from diagnosis may also be obtained.

After completion of study treatment, patients are followed up every 3 months.


Inclusion Criteria:



- Histologically confirmed diagnosis of a solid tumor for which no curative therapy
exists

- Measurable or evaluable disease

- ECOG performance status ≤ 2

- Prior chemotherapy is allowed. Patients must not have received chemotherapy for 3
weeks prior to the initiation of study treatment and must have full recovery from any
acute effects of any prior chemotherapy. Patients must not have had nitrosoureas or
mitomycin C for 6 weeks prior to the initiation of study treatment.

- Prior exposure to approved receptor tyrosine kinase inhibitors is permitted. At least
5 half-lives must have elapsed since the completion of the kinase inhibitor and the
initiation of study treatment.

- Prior radiation therapy is allowed. Patients must not have received any radiation
within 3 weeks prior to the initiation of study treatment. Patients may not have
areas of irradiated marrow exceeding 40% of bone marrow volume.

- Prior experimental (non-FDA approved) therapies and immunotherapies are allowed.
Patients must not have received these therapies for 3 weeks prior to the initiation
of study treatment and must have full recovery from any acute effects of these
therapies.

- Prior exposure to veliparib (ABT-888) or other PARP inhibitors is permitted. Prior
exposure to cyclin-dependent kinase inhibitors other than dinaciclib (SCH727965) is
permitted.

- Absolute neutrophil count ≥ 1,500/mm^3

- Hgb > 9.0 g/dL

- Platelet count ≥ 100,000/mm^3

- Total bilirubin < 1.5 mg/dL

- AST (SGOT)/ALT (SGPT) ≤ 2.5 times the institutional upper limit of normal (ULN) (for
patients with known liver metastases, AST and ALT ≤ 5 times ULN)

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- PT/INR and PTT ≤ 1.5 times ULN

- The effects of ABT-888 and SCH727965 on the developing human fetus are unknown. For
this reason, women of childbearing 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 participating in this study, she should
inform her treating physician immediately. Additionally, if a man suspects that he
has fathered a child while taking study agents, he should also inform his treating
physician immediately.

- Eligible patients in the dose escalation phases of the trial must agree to biopsies
of normal skin, unless they undergo optional tumor biopsies. Patients enrolled to the
expanded cohorts must agree to tumor sampling. Patients on anticoagulation must be
able to hold warfarin or low molecular weight heparin for a sufficient amount of time
to make skin and tumor biopsies safe to perform. PT/INR and PTT should be < 1.5 times
the institutional upper limit of normal prior to performance of skin or tumor
biopsies, with values re-checked after the eligibility screen as medically indicated.

- Patients must be able to swallow pills

- Patients enrolling in the BRCA-deficient cohort must have a documented BRCA1or BRCA2
germline mutation

- All patients must agree to provide an archival tissue block or paraffin sample from
archival tissue block (approximately 10 sections) for use in pharmaco dynamic
correlative studies; however, patients are not considered ineligible if archival
tumor is not available

- Ability to understand and the willingness to sign a written informed consent
document. Subjects must be willing to adhere to dose and visit schedules.

Exclusion Criteria:

- Patients must not receive any other anti-cancer therapy (cytotoxic, biologic,
radiation, or hormonal other than for replacement) while on this study except for
medications that are prescribed for supportive care but may potentially have an
anti-cancer effect (i.e. megestrol acetate, bisphosphonates). In addition, men
receiving treatment for prostate cancer will be maintained at castrate levels of
testosterone by continuation of luteinizing-releasing hormone agonists.

- Patients with known active brain metastases are excluded. Patients with a history of
CNS metastases that have been treated must be stable with no symptoms for > 3 months
after completion of that treatment and off steroid treatment, with image
documentation required prior to study enrollment.

- Patients with active seizure or a history of seizure

- Any patient requiring chronic maintenance of white blood cell counts or granulocyte
counts through the use of growth factor support (e.g. Neulasta®, Neupogen®)

- Patients who have previously received SCH727965

- Patients enrolling in Part 2 are excluded if they have a known allergy to platinum
drugs (cisplatin or carboplatin)

- Patients with other medical conditions judged by the investigator to be clinically
relevant in the setting of this study, which may include active infectious processes,
intractable emesis, or chronic diarrheal disease

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

- Pregnant women are excluded from this study because ABT-888 and SCH727965 are
anti-proliferative agents with the potential for teratogenic or abortifacient
effects. Because there is an unknown but potential risk of adverse events in nursing
infants secondary to treatment of the mother with ABT-888 and SCH727965,
breastfeeding should be discontinued if the mother is treated with ABT-888 and
SCH727965. These potential risks may also apply to other agents used in this study.

- Patients with prior seizure history who have experienced a seizure within the three
months prior to enrollment are excluded

- Subjects with a known allergy to lidocaine

- Subjects on a potent CYP3A4 inhibitor or CPY3A4 inducer who cannot be changed to
another medication are excluded

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended phase 2 dose of veliparib/dinaciclib with or without carboplatin determined by dose-limiting toxicities graded according to the NCI Common Terminology Criteria for Adverse Events (version 4.0)

Outcome Description:

Frequency tables of worst grade of adverse event, drug-related adverse events, and worst grade of laboratory value will be presented by dose cohort.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Geoffrey Shapiro

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-03458

NCT ID:

NCT01434316

Start Date:

November 2011

Completion Date:

Related Keywords:

  • brca1 Mutation Carrier
  • brca2 Mutation Carrier
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms

Name

Location

Dana-Farber Cancer Institute Boston, Massachusetts  02115