Olaparib + Ceralasertib for Recurrent Osteosarcoma
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: Dana-Farber Cancer Institute
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?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
What data supports the idea that Olaparib + Ceralasertib for Recurrent Osteosarcoma is an effective drug?
The available research does not provide specific data on the effectiveness of Olaparib + Ceralasertib for Recurrent Osteosarcoma. Instead, it discusses the challenges and limited success of current treatments for osteosarcoma, especially in cases of relapse or metastasis. While there are mentions of novel therapies being developed, no specific outcomes or data points for Olaparib + Ceralasertib are provided. Therefore, we cannot conclude its effectiveness based on the information available.
15111415Is the drug combination of Ceralasertib and Olaparib promising for treating recurrent osteosarcoma?
Yes, the drug combination of Ceralasertib and Olaparib is promising because Olaparib has shown success in treating ovarian cancer by targeting cancer cells with faulty DNA repair mechanisms. This suggests it could be effective in other cancers like osteosarcoma that may have similar vulnerabilities.
234712What safety data exists for Olaparib and Ceralasertib in treating recurrent osteosarcoma?
The provided research does not contain safety data for Olaparib or Ceralasertib in the treatment of recurrent osteosarcoma. The studies focus on osimertinib and apatinib, which are different drugs used for other conditions. Further research specifically on Olaparib and Ceralasertib is needed to answer this question.
6891013Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you must stop all current medications, but there are specific requirements. You must stop using certain drugs like potent CYP3A inhibitors and inducers, and herbal medications, with a washout period of five half-lives or 3 weeks for St. John's Wort. Additionally, you cannot have taken cytotoxic chemotherapy, hormonal or non-hormonal targeted therapy within 21 days, or immunotherapy within 42 days before starting the trial. Please consult with the study team for guidance on your specific medications.
Eligibility Criteria
This trial is for people aged 12-40 with osteosarcoma that has returned or didn't respond to treatment. They must weigh over 40 kg, have a life expectancy of at least 16 weeks, and be able to swallow pills. Women must not be pregnant or breastfeeding and use effective contraception. Men should also use barrier contraception.Inclusion Criteria
I have lung disease on one side and can provide a sample of my tumor.
I weigh more than 40 kg.
I am between 13 and 40 years old.
Surgery for my disease is not possible without major risks and no other standard treatments are available.
I am mostly active and can care for myself, with no recent decline.
My kidney, liver, and bone marrow are functioning normally.
My osteosarcoma was confirmed through tissue examination.
My lung cancer has come back at least once but is still only in my lungs.
My condition has not improved or has worsened despite treatment.
I have recovered from side effects of my previous cancer treatments.
I can swallow pills whole.
Exclusion Criteria
I am not taking any strong CYP3A enzyme stimulators.
I don't have any lasting side effects from previous treatments that are moderate or worse.
I have not had heart disease in the past 6 months.
I do not have any uncontrolled illnesses like heart failure or severe infections.
I am not taking strong or moderate drugs that affect liver enzymes.
I have been diagnosed with ataxia telangiectasia.
My heart's pumping ability is below normal.
I have not had immunotherapy in the last 42 days.
I have been diagnosed with MDS, AML, or have symptoms suggesting these conditions.
I have not had major surgery in the last 2 weeks.
I am not pregnant or breastfeeding.
I am not using effective birth control.
I plan to use herbal medications within a week before starting the study treatment.
I have ongoing issues with nausea, vomiting, or have had major surgery on my intestines.
I have brain metastases that are causing symptoms and are not under control.
I experience significant drops in blood pressure when standing.
Participant Groups
The effectiveness of two drugs, Olaparib and Ceralasertib, is being tested on patients with recurrent osteosarcoma. The study aims to see how well these drugs work when other treatments have failed or the cancer has come back.
1Treatment groups
Experimental Treatment
Group I: Olaparib-CeralasertibExperimental Treatment2 Interventions
Unresectable 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 2 times a day on days 1-14 in 28-day study cycles.
Patients can remain on treatment for up to 2 years if disease progression has not occurred.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
UCSF Benioff Children's Hospital; UCSF Pediatrics Hematology OncologySan Francisco, CA
Dana Farber Cancer InstititeBoston, MA
Memorial Sloan KetteringNew York, NY
MD AndersonHouston, TX
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Who is running the clinical trial?
Dana-Farber Cancer InstituteLead Sponsor
Osteosarcoma InstituteCollaborator
AstraZenecaIndustry Sponsor
References
Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. [2021]To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma.
Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. [2016]Olaparib (Lynparza™; AZD2281) is a potent PARP-1 and PARP-2 inhibitor with biologic activity in ovarian cancer as well as other solid tumors. It has been tested in Phase I and II trials and has single-agent activity in both germline BRCA mutated and sporadic ovarian cancer. Phase III trials assessing the efficacy of olaparib in the maintenance setting following first line and platinum-sensitive recurrence are underway for patients with a germline BRCA mutation, given the inherent molecular compatibility with the drug's mechanism of action.
Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. [2016]Olaparib (Lynparza™) is a first-in-class, orally-active, small molecule, poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. In the EU, the capsule formulation of olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, BRCA-mutated (germline and/or somatic), high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. This approval was based on the results of study 19, a randomized phase II trial in 265 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer (HGSOC) who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Study 19 met its primary endpoint by demonstrating a significant improvement in progression-free survival in patients receiving olaparib compared with those receiving placebo. Moreover, a preplanned retrospective analysis identified those patients with a BRCA mutation (who comprised one-half of the overall study population) as being the subgroup that derived the greatest clinical benefit from olaparib. Single-agent olaparib was generally well tolerated, with the majority of adverse events being of mild to moderate severity and not requiring interruption of treatment. Fatigue, anaemia and neutropenia were the most frequently reported severe (grade ≥3) adverse events. An as yet unapproved tablet formulation of olaparib that has a lower pill burden than the capsule formulation is currently being investigated in phase III clinical studies.
Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy.
Novel insights and therapeutic interventions for pediatric osteosarcoma. [2017]High-grade osteosarcomas are the most common primary malignant tumors of bone. With complete surgical resection and multi-agent chemotherapy up to 70% of patients with high-grade osteosarcomas and localized extremity tumors can become long-term survivors. The prognosis, however, is poor for patients with nonresectable, primary metastatic or relapsed disease. Outcome is essentially unchanged for three decades. Herein, we describe selected novel insights into the genomics, biology and immunology of the disease and discuss selected strategies, which hold promise to overcome the current stagnation in the therapeutic success in childhood osteosarcoma.
FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. [2022]On March 30, 2017, the U.S. Food and Drug Administration (FDA) approved osimertinib for the treatment of patients with metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive, non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed following EGFR tyrosine kinase inhibitor (TKI) therapy. Approval was based on demonstration of a statistically significant difference in the primary endpoint of progression-free survival (PFS) when comparing osimertinib with chemotherapy in an international, multicenter, open-label, randomized trial (AURA3). In this confirmatory trial, which enrolled 419 patients, the PFS hazard ratio for osimertinib compared with chemotherapy per investigator assessment was 0.30 (95% confidence interval 0.23-0.41), p < .001, with median PFS of 10.1 months in the osimertinib arm and 4.4 months in the chemotherapy arm. Supportive efficacy data included PFS per blinded independent review committee demonstrating similar PFS results and an improved confirmed objective response rate per investigator assessment of 65% and 29%, with estimated median durations of response of 11.0 months and 4.2 months, in the osimertinib and chemotherapy arms, respectively. Patients received osimertinib 80 mg once daily and had a median duration of exposure of 8 months. The toxicity profile of osimertinib compared favorably with the profile of other approved EGFR TKIs and chemotherapy. The most common adverse drug reactions (>20%) in patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, and fatigue. Herein, we review the benefit-risk assessment of osimertinib that led to regular approval, for patients with metastatic NSCLC harboring EGFR TKI whose disease has progressed on or after EGFR TKI therapy.
Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours.
Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. [2022]Osimertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted for both EGFR sensitizing mutations and T790M resistance mutation in patients with non-small-cell lung cancer (NSCLC). We assessed efficacy and safety of osimertinib in patients with pretreated NSCLC in a real-world setting.
Anorexia, Hypertension, Pneumothorax, and Hypothyroidism: Potential Signs of Improved Clinical Outcome Following Apatinib in Advanced Osteosarcoma. [2022]Apatinib, a specific tyrosine kinase inhibitor (TKI) that targets mainly vascular endothelial growth factor receptor-2 (VEGFR-2) as well as Ret, c-Kit and c-Src, has been assessed in patients with advanced osteosarcoma (phase II), the primary report of which has been published in PMID 30559126. This sub-study explored the potential signs of Adverse Events (AEs) for apatinib-treated osteosarcoma.
Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan. [2022]Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan.
Role of TKI for Metastatic Osteogenic Sarcoma. [2021]Osteosarcomas (OS) belong to a large family of mesenchymal tumor entities which exhibit heterogenous histological, genetic, and molecular features. Current OS treatment regimen consists of the combination of surgery and intensive multi-agent chemotherapy. Ever since the introduction of chemotherapy, 5-year survival rate among OS patients has improved to 60-75%. However, 30-35% of OS patients are associated with pulmonary metastasis and relapse, which have significantly poor prognosis, with an overall 5-year survival rate of about 20%. The fact that OS are both rare forms of cancer and highly heterogeneous may explain why patients' survival has not improved in the past three decades, especially for metastatic/relapsed and unresectable osteosarcomas. Patients who experience relapse with metastatic disease have limited therapeutic options, often receiving additional cytotoxic therapy such as ifosfamide and etoposide and/or carboplatin or gemcitabine plus docetaxel. Novel precise OS-targeted thrapies are being developed with the hope of improving metastatic/relapsed OS prognosis. This review provides an overview of the most updated targeted therapies in relapsed/metastatic osteosarcoma and dicusses some clinical options in order to improve progression-free survival.
DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment. [2021]With the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need.
Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. [2023]This multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC).
Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma. [2023]Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer that predominantly affect the young. Despite aggressive multimodal treatment, survival has not improved significantly over the past four decades. Clinical efficacy has historically been observed for some mono-Receptor Tyrosine Kinase (RTK) inhibitors, albeit in small subsets of OS and ES patients. Clinical efficacy in larger groups of OS or ES patients was reported recently with several newer generation multi-RTK inhibitors. All these inhibitors combine a strong anti-angiogenic (VEGFRs) component with simultaneous inhibition of other key RTKs implicated in OS and ES progression (PDGFR, FGFR, KIT and/or MET). However, despite interesting clinical data, none of these agents have obtained a registration for these indications and are thus difficult to implement in routine OS and ES patient care. It is at present also unclear which of these drugs, with largely overlapping molecular inhibition profiles, would work best for which patient or subtype, and treatment resistance almost uniformly occurs. Here, we provide a critical assessment and systemic comparison on the clinical outcomes to the six most tested drugs in this field in OS and ES to date, including pazopanib, sorafenib, regorafenib, anlotinib, lenvatinib and cabozantinib. We pay special attention to clinical response evaluations in bone sarcomas and provide drug comparisons, including drug-related toxicity, to put these drugs into context for OS and ES patients, and describe how future trials utilizing anti-angiogenic multi-RTK targeted drugs could be designed to ultimately improve response rates and decrease toxicity.
A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design? [2023]To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.