Prexasertib and Olaparib in Treating Patients with Metastatic or Unresectable Solid Tumors

Status: Active

Description

This phase I trial studies the side effects and best dose of prexasertib and olaparib in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. Prexasertib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Written informed consent obtained prior to any study-specific procedures not considered part of routine medical care
  • Patients must have histologically confirmed solid tumor that is metastatic or unresectable, and there is no available therapy likely to convey clinical benefit; for enrollment to expansion cohort 2, patients must have high-grade serous ovarian or fallopian tube cancer
  • For enrollment to expansion cohort 2, patients must have a documented BRCA1 or BRCA2 mutation by a Clinical Laboratory Improvement Act (CLIA) certified lab
  • Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; measurable disease is defined as 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
  • There are no limits on prior lines of therapy; however, patients must have recovered to eligibility levels from prior toxicity or adverse events as a result of previous treatment prior to entering the study (except alopecia)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Absolute neutrophil count >= 1,500/microliters (completed within 14 days prior to the date of registration)
  • Platelets >= 100,000/microliters (completed within 14 days prior to the date of registration)
  • White blood cells (WBC) >= 3 x 10^9/L (completed within 14 days prior to the date of registration)
  • Hemoglobin >= 10 g/dL (completed within 14 days prior to the date of registration)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (completed within 14 days prior to the date of registration)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN or =< 5 x institutional ULN in the setting of liver metastases (mets), (completed within 14 days prior to the date of registration)
  • Creatinine =< 1.5 X institutional ULN (completed within 14 days prior to the date of registration) OR
  • Creatinine clearance >= 60 mL/min by Cockcroft-Gault equation for participants with creatinine levels above institutional normal (completed within 14 days prior to the date of registration)
  • The effects of prexasertib and olaparib on the developing human fetus are unknown; for this reason, women of childbearing potential and male patients with partners of childbearing potential must agree to use two highly effective forms of contraception prior to study entry, for the duration of study participation, and for 3 months after completion of study; 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 for 3 months after completion of prexasertib and olaparib administration; 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
  • Women of childbearing potential enrolling on study must have a negative serum pregnancy test prior to registration * Childbearing potential is defined as women who are not postmenopausal (defined as amenorrheic for >= 12 months following cessation of any exogenous hormonal treatments; luteinizing hormone [LH] and follicle stimulating hormone [FSH] levels in the postmenopausal range for women under 50; radiation-induced oophorectomy with last menses > 12 months prior; or chemotherapy-induced menopause with last menses > 12 months prior) or surgically sterile (bilateral oophorectomy or hysterectomy)
  • Ability to understand and the willingness to sign a written informed consent document; patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
  • Patients must be able to tolerate oral medications and not have gastrointestinal processes that would preclude absorption of olaparib
  • Patients enrolled to expansion cohort 2 must have at least one site of tumor amenable to percutaneous biopsy and be willing to undergo biopsy
  • Patients enrolled to expansion cohort 2 must have previously received a PARP inhibitor with clinical benefit of at least 6 months

Exclusion Criteria

  • Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; patients who have received prior PARP inhibitor will not be excluded; patients who have received prior CHK1 inhibitor will be excluded
  • Participants who have undergone major surgery within 14 days of starting the study treatment, or participants who have not recovered to baseline status from the effects of major surgery received more than 14 days prior
  • Patients who are receiving any other investigational agents
  • Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients with brain metastatic disease that has previously been treated and remained stable on MRI >= 2 months prior to enrollment, without steroids or anti-epileptic medications; these patients may be enrolled at the discretion of the principal investigator
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to prexasertib or olaparib
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled seizures, myocardial infarction within the past 3 months, superior vena cava syndrome, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), or psychiatric illness/social situations that would limit compliance with study requirements; additionally, patients with other co-morbid disease or metabolic dysfunction that would render the subject at high risk for treatment complications may be excluded at the discretion of the principal investigator in the interest of patient safety
  • The effects of prexasertib and olaparib on the developing human fetus are unknown; for this reason, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with prexasertib and olaparib, breastfeeding women are also excluded
  • Known human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with prexasertib and olaparib; in addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy
  • Participants with known active hepatitis B or C
  • Participants who have received a previous allogeneic bone marrow transplant
  • Consistent corrected QT (QTc) > 470 msec on more than one screening electrocardiograms (ECGs); patients with a history of long QTc syndrome or personal or family history of ventricular arrhythmias will be excluded
  • Participants with involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Participants receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP3A4 are ineligible; 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
  • Participants with a history of myelodysplastic syndrome or acute myeloid leukemia
  • Participants with evidence of pneumonitis on scans at screening will be excluded

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Khanh Tu Do
Phone: 617-632-6992
Email: KhanhT_Do@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Khanh Tu Do
Phone: 617-632-6992
Email: KhanhT_Do@dfci.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Establish the safety profile, tolerability, and maximum tolerated dose (MTD) of the combination of prexasertib (LY2606368) and olaparib, including characterization of the dose-limiting toxicity (DLT).

II. Assess the pharmacokinetics (PK) of the combination of prexasertib and olaparib.

SECONDARY OBJECTIVES:

I. Determine anti-tumor effects of the combination of prexasertib and olaparib.

II. Assess for phosphorylated (phospho)-CDK expression in tumor biopsies as a marker of prexasertib effect and downstream marker of target engagement.

III. Assess changes in RAD51 focus formation and gamma-H2AX expression on-treatment biopsies compared to pre-treatment biopsies to confirm combinatorial proof-of-mechanism.

EXPLORATORY OBJECTIVES:

I. Generate an expansion cohort of patient-derived poly (ADP-ribose) polymerase (PARP) inhibitor-resistant BRCA1/2-mutant high-grade serous ovarian carcinoma organoid cultures for further characterization of deoxyribonucleic acid (DNA) damage repair defects and changes in replication fork stability.

OUTLINE: This is a dose-escalation study of olaparib and prexasertib.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-5 and 15-19 and prexasertib intravenously (IV) over 1 hour on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Khanh Tu Do

Trial IDs

Primary ID 16-573
Secondary IDs NCI-2017-00488
Clinicaltrials.gov ID NCT03057145