Olaparib With Ceralasertib in Recurrent Osteosarcoma

  • STATUS
    Recruiting
  • End date
    Jun 1, 2025
  • participants needed
    63
  • sponsor
    Dana-Farber Cancer Institute
Updated on 27 January 2021

Summary

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

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.

Details
Condition Osteosarcoma, Sarcoma, Recurrent Osteosarcoma, Sarcoma (Pediatric), Soft Tissue Sarcoma, Osteosarcoma Recurrent, bone sarcoma
Treatment olaparib, Ceralasertib
Clinical Study IdentifierNCT04417062
SponsorDana-Farber Cancer Institute
Last Modified on27 January 2021

Eligibility

Yes No Not Sure

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
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