Clinical Trials /

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

NCT03057145

Description:

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

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Combination Study of Prexasertib and Olaparib in Patients With Advanced Solid Tumors
  • Official Title: Phase 1 Combination Study of Prexasertib (LY2606368), CHK1 Inhibitor, and Olaparib, PARP Inhibitor, in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 16-573
  • NCT ID: NCT03057145

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
PrexasertibLY2606368Prexasertib Combine with Olaparib
OlaparibLynparzaPrexasertib Combine with Olaparib

Purpose

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

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      intervention and also tries to define the appropriate dose of the investigational
      intervention to use for further studies. "Investigational" means that the intervention is
      being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved LY2606368 as a treatment for
      any disease.

      The FDA (the U.S. Food and Drug Administration) has approved Olaparib for ovarian cancer but
      it has not been approved for other uses.

      LY2606368 is a checkpoint kinase 1 (CHK1) inhibitor that is being developed as a treatment
      for patients with advanced cancer. CHK1 inhibitors work by preventing the cancer cells from
      being able to repair damaged DNA (one of the building blocks of a cell) which then leads to
      cell death.

      Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. PARP is a protein in the body
      that repairs damage to DNA. In cells that are rapidly growing such as cancer cells, blocking
      repair of DNA may be of benefit, since it will cause the cell to die.

      In this research study, the investigators are combining LY2606368 with Olaparib in the hopes
      that it will be a safe combination and that the LY2606368 will enhance how the cancer will
      respond to Olaparib. In previous laboratory studies performed by treating cancer cells with a
      CHK1 inhibitor and a PARP inhibitor, it was found that the CHK1 inhibitor was successful in
      increasing efficacy.
    

Trial Arms

NameTypeDescriptionInterventions
Prexasertib Combine with OlaparibExperimentalOlaparib 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
  • Prexasertib
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  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
             (see Section 5.5.2) 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;
             LH and 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.

        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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:2 months
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Secondary Outcome Measures

Measure:Dose Limiting Toxicity as assessed by CTCAEv4.0
Time Frame:1 month
Safety Issue:
Description:
Measure:Pharmacokinetic Sampling - Peak Plasma Concentration (Cmax)
Time Frame:2 months
Safety Issue:
Description:
Measure:Pharmacokinetic Sampling - Area Under the Plasma Concentration versus Time Curve (AUC)
Time Frame:2 months
Safety Issue:
Description:
Measure:Anti-Tumor Effects Of The Combination Of Prexasertib And Olaparib by RECIST 1.1
Time Frame:2 months
Safety Issue:
Description:
Measure:Phospho-CDK Expression In Tumor Biopsies As A Marker Of Prexasertib Effect And Downstream Marker Of Target Engagement
Time Frame:1 month
Safety Issue:
Description:
Measure:RAD51 Focus Formation and γ-H2AX Expression in tumor biopsies Post-Olaparib And Post-Combination Treatment as a marker of DNA damage
Time Frame:1 month
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Khanh Do

Trial Keywords

  • Solid Tumor

Last Updated

August 12, 2019