Clinical Trials /

Olaparib With Ceralasertib in Recurrent Osteosarcoma

NCT04417062

Description:

This study is being done in order to evaluate the effectiveness of using two drugs (olaparib and ceralasertib) to treat patients with osteosarcoma that has not responded to treatment or has come back after treatment The names of the study drugs involved in this study are: - Olaparib - Ceralasertib

Related Conditions:
  • Osteosarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib With Ceralasertib in Recurrent Osteosarcoma
  • Official Title: Phase II Trial of Olaparib in Combination With Ceralasertib in Patients With Recurrent Osteosarcoma

Clinical Trial IDs

  • ORG STUDY ID: 20-086
  • NCT ID: NCT04417062

Conditions

  • Osteosarcoma
  • Osteosarcoma Recurrent

Interventions

DrugSynonymsArms
OlaparibLynparzaOlaparib-Ceralasertib
CeralasertibAZD6738Olaparib-Ceralasertib

Purpose

This study is being done in order to evaluate the effectiveness of using two drugs (olaparib and ceralasertib) to treat patients with osteosarcoma that has not responded to treatment or has come back after treatment The names of the study drugs involved in this study are: - Olaparib - Ceralasertib

Detailed Description

      This is a single arm, phase 2, open-label clinical trial to evaluate the use of olaparib in
      combination with ceralasertib in 2 cohorts of patients aged 12-30 with recurrent
      osteosarcoma.

      The research study procedures include screening for eligibility, study treatment, evaluations
      and follow-up visits.

        -  Cohort 1: Participants with unresectable osteosarcoma (unable to remove with surgery)

        -  Cohort 2: Participants with lung only resectable osteosarcoma (able to remove with
           surgery)

      Participants will be given a drug diary to document information about the study treatment and
      study calender with information about what to expect during and between study visits. The
      names of the study drugs involved in this study are:

        -  Olaparib

        -  Ceralasertib

      Each treatment cycle lasts 28 days and participants will receive study treatment up to 24
      cycles (2 years).

      It is expected that about 63 people will take part in this research study.

        -  The study is looking to test: whether olaparib and ceralasertib given together are
           effective in patients with recurrent or refractory osteosarcoma.

        -  how safe and how well tolerated olaparib and ceralasertib are when given together in
           patients with recurrent or refractory osteosarcoma.

        -  markers in the blood and in tumor tissue to see if there are certain features of the
           tumor that may indicate this combination of drugs is effective or not effective.

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

      This is the first time that Ceralasertib will be given to children.

      The U.S. Food and Drug Administration (FDA) has not approved olaparib for recurrent
      osteosarcoma but it has been approved for other uses.
    

Trial Arms

NameTypeDescriptionInterventions
Olaparib-CeralasertibExperimentalUnresectable disease (can not be surgically removed) will be enrolled into Cohort 1 and Resectable disease (can be surgically removed) which is limited only to the lung parenchyma will be enrolled into Cohort 2. Olaparib at a predetermined dose orally 2 times a day on days 1-28 Ceralasertib will be given at a predetermined dose orally once a day on days 1-7 in 28-day study cycles. Patients can remain on treatment for up to 2 years if disease progression has not occurred.
  • Olaparib
  • Ceralasertib

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of informed consent prior to any study specific procedures.

          -  Age > 12 years and ≤ 30 years

          -  Weight > 40 kg

          -  Lansky/Karnofsky performance status ≥ 60% for participants ≥16 years of age and Lansky
             ≥ 60% for participants <16 years of age (see Appendix B) within 28 days prior to
             enrollment with no deterioration over the previous 2 weeks. Please note, patients who
             have had prior orthopedic surgery as part of their osteosarcoma therapy should not be
             considered non-ambulatory in their performance status if their non-ambulatory status
             is the result of surgery.

          -  Estimated life expectancy of ≥16 weeks.

          -  Diagnosis requirement

               -  All participants must have histologic verification of osteosarcoma at original
                  diagnosis or relapse

               -  All participants must have disease that has relapsed or has become refractory to
                  conventional therapy

          -  Cohort 1 Requirements

               -  Participants must have measurable disease according to RECIST v1.1. At least one
                  measurable lesion that can be accurately assessed at baseline by computed
                  tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated)
                  and is suitable for repeated assessment as per RECIST v1.1.

               -  Surgical resection of all possible sites of disease is not feasible or will
                  result in major and / or unacceptable morbidity and no other standard of care
                  treatment is available per assessment of the treating investigator

               -  Participants must have archival tumor specimen available for submission.

          -  Cohort 2 Requirements

               -  Participants must have had at least one episode of disease recurrence limited to
                  the lung parenchyma with no limits on the number of episodes of recurrence

               -  Surgical resection of all possible sites of suspected pulmonary metastases in
                  order to achieve a complete remission is considered feasible by treating
                  physicians

               -  Participants with pulmonary disease on only one side must have archival tumor
                  specimen available for submission.

          -  Participants must have fully recovered from the acute toxic effects of all prior
             anti-cancer therapy. Participants must meet the following minimum washout periods
             prior to registration:

               -  Myeloid growth factors: At least 14 days following the last dose of long-acting
                  growth factor (e.g. Neulasta) or 7 days following short-acting growth factor.

               -  Stem Cell or Autologous T Cell Infusion: At least 42 days must have elapsed after
                  stem cell or autologous T cell infusion.

               -  Participants must not have previously received and progressed on olaparib or
                  other PARP inhibitor therapy.

               -  Participants must not have previously received and progressed on ceralasertib or
                  other ATR inhibitor therapy.

          -  Participants must have normal organ function as defined below.

               -  Bone Marrow Function

                    -  Absolute neutrophil count ≥1,250/uL

                    -  Platelets ≥100,000/uL (with no platelet transfusions within the last 28
                       days)

                    -  Hemoglobin ≥9 g/dL (with no blood transfusion or erythpoetin use within past
                       28 days)

               -  Hepatic Function

                    -  Total bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert's
                       syndrome

                    -  AST or ALT ≤ 2.5 x ULN, unless liver metastases are present in which case
                       they cannot be > 5x ULN

               -  Renal Function

                  --- A serum creatinine based on age/gender as follows:

               -  Age Maximum Serum Creatinine (mg/dL)

                    -  Age: 12 to <13 years Maximum Serum Creatinine (mg/dL): Male 1.2 Female 1.2

                    -  Age: 13 to < 16 years Maximum Serum Creatinine (mg/dL): Male 1.5 Female1.4

                    -  Age: ≥ 16 years Maximum Serum Creatinine (mg/dL): Male 1.7 Female 1.4 OR

                    -  Creatinine clearance ≥ 70 mL/min/1.73 m2 for participants with creatinine
                       levels above institutional normal

          -  Participants must be able to swallow intact pills.

          -  Female participants must have a negative serum or urine pregnancy test within 28 days
             of study treatment and confirmed prior to treatment on Cycle 1 Day 1.

          -  Females must not be breast feeding. Women of childbearing potential and their
             partners, who are sexually active, must agree to the use of 2 highly effective forms
             of contraception in combination from the signing of the informed consent, throughout
             the period of taking study treatment and for at least 1 month after last dose of study
             drug(s), or they must totally/truly abstain from any form of sexual intercourse.

          -  Male patients who are sexually active must be willing to use barrier contraception for
             the duration of the study and for 1 week after the last study drug administration,
             with all sexual partners. Male patients must use a condom during treatment and for 6
             months after the last dose of study drug(s) when having sexual intercourse with a
             pregnant woman or with a woman of childbearing potential and must not donate sperm for
             6 months after the last dose of study drug. Female partners of male patients should
             also use a highly effective form of contraception for 6 months after the last dose of
             study drug(s) if they are of childbearing potential. True abstinence for either sex is
             an acceptable form of contraception and must be documented as such.

          -  Ability to understand and/or the willingness of the patient (or parent or legally
             authorized representative, if minor) to provide informed consent, documented using an
             institutionally approved informed consent procedure.

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations.

        Exclusion Criteria:

          -  Participants with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) or
             features suggestive of MDS/AML.

          -  Patients with a known diagnosis of ataxia telangiectasia.

          -  Cytotoxic chemotherapy, hormonal or non-hormonal targeted therapy within 21 days of
             Cycle 1 Day 1 is not permitted (a duration of five half times is allowed for patients
             treated with noncytotoxic drugs).

          -  Immunotherapy within 42 days of Cycle 1 Day 1.

          -  Prior TOTAL lung radiation. If prior radiation included lung then radiation must have
             been completed 12 weeks before Cycle 1 Day 1 AND V20 (% of lung that received 20Gy)
             must not exceed 25% OR the mean lung dose must be less than 5Gy. Even if these
             eligibility criteria are met, patients who have received prior radiotherapy including
             lung are only eligible after review and approval by the study PI.

          -  Palliative radiotherapy to sites not including lung must have been completed 7 or more
             days before Cycle 1 Day 1 (with the following exception: patients receiving radiation
             to more than 30% of the bone marrow or with a wide field of radiation must have been
             completed 4 weeks before C1D1. The patient can receive a stable dose of
             bisphosphonates or denosumab for bone metastases, before and during the study as long
             as these were started at least 5 days prior to the study treatment.

          -  Receiving, or having received during the 14 days prior to Cycle 1 Day 1,
             corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason.
             Topical, inhaled or ophthalmic steroid administration is acceptable.

          -  Major surgery within 2 weeks of starting study treatment: patients must have recovered
             from any effects of any major surgery.

          -  Any other malignancy which has been active or treated within the past three years,
             with the exception of cervical intra-epithelial neoplasia and non-melanoma skin
             cancer, Ductal Carcinoma in Situ, stage 1 grade 1 endometrial carcinoma, or other
             solid tumors curatively treated with no evidence of disease for ≥ 5 years prior to
             study entry.

          -  With the exception of alopecia and CTCAE grade 2 neuropathy, any unresolved toxicities
             from prior therapy ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2.

          -  Patient with resting left-ventricular ejection fraction (LVEF) < 50% measured by
             ECHO/MUGA

          -  Any of the following cardiac diseases currently or within the last 6 months (by New
             York Heart Association (NYHA) ≥ Class 2 where applicable):

               -  Unstable angina pectoris

               -  Congestive heart failure or known reduced LVEF < 55%

               -  Acute myocardial infarction

               -  Conduction abnormality not controlled with pacemaker or medication e.g. complete
                  left bundle branch block, third degree heart block

               -  Significant ventricular or supraventricular arrhythmias e.g. (patients with
                  chronic rate controlled atrial fibrillation in the absence of other cardiac
                  abnormalities are eligible)

               -  Patients at risk of brain perfusion problems, e.g., medical history of carotid
                  stenosis or pre-syncopal or syncopal episodes, history of TIAs

               -  Uncontrolled hypertension (grade 2 or above) requiring clinical intervention

          -  Corrected QT interval (QTc) ≤ 470msec obtained from 3 electrocardiograms (ECGs) 2-5
             minutes apart using the Fredericia formula

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as congestive heart failure, unstable angina pectoris, acute
                  myocardial infarction, hypokalaemia, congenital long QT syndrome, immediate
                  family history of long QT syndrome or unexplained sudden death under 40 years of
                  age, conduction abnormality not controlled with pacemaker or medication.

          -  Patients with relative hypotension (less than 5th percentile for age/height/sex or
             systolic and/or diastolic blood pressure >15% below baseline) or clinically relevant
             orthostatic hypotension (a fall in systolic blood pressure of at least 20 mm Hg within
             3 minutes of standing compared to blood pressure obtained from sitting/supine
             position).

          -  Concomitant use of known potent cytochrome P (CYP) 3A inhibitors (eg.itraconazole,
             telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
             cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate
             CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil).
             The required washout period prior to starting study treatment is five half-lives.

          -  Concomitant use of known potent (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin,rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) CYP3A
             inducers (eg.bosentan, efavirenz, modafinil). The required washout period prior to
             starting study treatment is five half-lives, except for St-Johns' wort, which is 3
             weeks.

        Patient has had prescription or non-prescription drugs or other products known to be CYP3A4
        and/or CYP2B6 substrates or CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic
        index. Exposure of other drugs metabolised by CYP3A4 and/or CYP2B6 may be reduced and
        additional monitoring may be required The use of herbal supplements or 'folk remedies' (and
        medications and foods that significantly modulate CYP3A activity) should be discouraged. If
        deemed necessary, such products may be administered with caution and the reason for use
        documented in the CRF. Please see Appendix E for further details.

          -  Patients should stop using herbal medications 7 days prior to first dose of study
             treatment.

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases or previous
             significant bowel resection, with clinically significant sequelae that would preclude
             adequate absorption of ceralasertib.

          -  Participants with a known hypersensitivity to olaparib or any of the excipients of the
             product or any contraindication to the combination anti-cancer agent as per local
             prescribing information.

          -  Participants with a known hypersensitivity to ceralasertib or any of the excipients of
             the product or any contraindication to the combination anti-cancer agent as per local
             prescribing information.

          -  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.

          -  As judged by the Investigator, any evidence of severe or uncontrolled systemic
             diseases that places the patient at unacceptable risk of toxicity or non-compliance.
             Examples include, but are not limited to, active bleeding diatheses, renal transplant,
             uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome,
             extensive bilateral lung disease on High Resolution CT scan, severe Parkinson's
             disease, active inflammatory bowel disease, psychiatric condition, or active infection
             including any patient known to have hepatitis B, hepatitis C and human
             immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or
             antiviral drugs.

        Screening for chronic conditions is not required.

          -  Patients with symptomatic uncontrolled brain metastases. Patients with a history of
             treated central nervous system (CMS) metastases are eligible provided they meet all of
             the following criteria: disease outside the CNS is present, no clinical evidence of
             progression since completion of CNSdirected therapy, minimum 3 weeks between
             completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥ 3)
             acute toxicity with no ongoing requirement for >10 mg of prednisolone per day or an
             equivalent dose of other corticosteroid. If on corticosteroids, the patient should be
             receiving a stable dose of corticosteroids, started at least 4 weeks prior to
             treatment.

          -  Female patients who are pregnant or breast-feeding.

          -  Male or female patients of reproductive potential who are not employing an effective
             method of birth control.

          -  Spinal cord compression or brain metastases unless treated, asymptomatic and stable
             and not requiring steroids for at least 4 weeks prior to start of study treatment.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort 1 Event Free at 4 months
Time Frame:4 months after start of protocol therapy
Safety Issue:
Description:Simon's two-stage design will be applied to the primary (binary) endpoint, event-free at 4-months. An event is defined as the occurrence of relapse, disease progression as defined by RECIST 1.1, or death from any cause.

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:2 years
Safety Issue:
Description:Radiographic response according to RECIST criteria. confidence interval on the proportion.
Measure:Event Free Survival
Time Frame:time from registration to the earlier of progression, relapse, or death due to any cause up to 4 years
Safety Issue:
Description:Kaplan-Meier curves using standard errors
Measure:Overall Survival
Time Frame:defined as the time from registration until death from any cause up to 4 years
Safety Issue:
Description:Kaplan-Meier curves
Measure:Cohort 2 Event Free Survival 12 months
Time Frame:12 months
Safety Issue:
Description:Within Cohort 2, calculate the proportion who are event-free at 12- months, as the total number event-free at 12-months divided by the number of evaluable patients.
Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0
Time Frame:enrollment until 30 days after last dose of study treatment up to 24 Months
Safety Issue:
Description:The number and proportion of adverse events will be tabulated by type and grade. This analysis will be performed overall and separately for Cohort 1 and 2. Within a given patient, a given adverse event will be counted only once at the highest grade.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Osteosarcoma
  • Osteosarcoma Recurrent

Last Updated

June 2, 2020