Combination Study of Prexasertib and Olaparib in Patients With Advanced Solid Tumors

NCT03057145 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 16-573
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is studying a combination of targeted therapies as a possible treatment for Advanced Solid Tumors. The study interventions involved in this study are:

• LY2606368
• Olaparib

Conditions

Solid Tumor

Keywords

Solid Tumor

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose

  Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  2 months

Secondary Outcomes (6)

• Dose Limiting Toxicity as assessed by CTCAEv4.0

  1 month

• Pharmacokinetic Sampling - Peak Plasma Concentration (Cmax)

  2 months

• Pharmacokinetic Sampling - Area Under the Plasma Concentration versus Time Curve (AUC)

  2 months

• Anti-Tumor Effects Of The Combination Of Prexasertib And Olaparib by RECIST 1.1

  2 months

• Phospho-CDK Expression In Tumor Biopsies As A Marker Of Prexasertib Effect And Downstream Marker Of Target Engagement

  1 month

Study Arms (1)

Prexasertib Combine with Olaparib

EXPERIMENTAL

* Olaparib will be administered orally on an intermittent schedule during each 28-day cycle. Exact administration schedule will depend on assigned dose level. * Prexasertib will be administered intravenously on Days 1 and 15 of a cycle

Drug: Prexasertib; Drug: Olaparib

Interventions

Prexasertib DRUG

LY2606368 is a checkpoint kinase 1 (CHK1) inhibitor that is being developed as a treatment for patients with advanced cancer

Also known as: LY2606368

Prexasertib Combine with Olaparib

Olaparib DRUG

Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor.

Also known as: Lynparza

Prexasertib Combine with Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained prior to any study-specific procedures not considered part of routine medical care.
• For enrollment to expansion cohort 2, patients must have high-grade serous ovarian or fallopian tube cancer and documentation of BRCA1 or BRCA2 mutation by a CLIA certified lab.
• Patients must have measurable disease by 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 ≥ 20mm (≥ 2cm) with conventional techniques or as ≥ 10mm (≥ 1cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
• 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).
• Age ≥18 years, as no dosing or adverse event data are currently available on the use of prexasertib in combination with olaparib in patients \< 18 years of age, children are excluded from this study.
• ECOG performance status 0-1. PERFORMANCE STATUS CRITERIA.
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count ≥ 1,500/microliters
• platelets ≥ 100,000/microliters
• white blood cells (WBC) ≥ 3 x 109/L
• hemoglobin ≥ 10 g/dL
• total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤2.5 x institutional ULN or ≤ 5 x institutional ULN in the setting of liver mets
• creatinine ≤ 1.5X institutional ULN OR
• creatinine clearance ≥60 mL/min by Cockcroft-Gault equation for participants with creatinine levels above institutional normal.

You may not qualify if:

• 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 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 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 QTc \> 470 msec on more than one screening 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. Please see Section 5.5.1 for further detail and required washout periods. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. 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 due to pulmonary toxicities associated with olaparib

Sponsors & Collaborators

• Geoffrey Shapiro, MD, PhD: lead
• Eli Lilly and Company: collaborator
• AstraZeneca: collaborator

Study Sites (1)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.

  PMID: 34904813 DERIVED

MeSH Terms

Interventions

prexasertib; olaparib

Study Officials

• Geoffrey Shapiro, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 10, 2017
• First Posted: February 17, 2017
• Study Start: March 10, 2017
• Primary Completion: February 25, 2020
• Study Completion: June 9, 2021
• Last Updated: September 2, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)