Olaparib + Ceralasertib for Recurrent Osteosarcoma

Not currently recruiting at 3 trial locations

Overseen By Katherine Janeway, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: MDS, AML, Ataxia telangiectasia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether two drugs, olaparib (Lynparza) and ceralasertib, can effectively treat osteosarcoma that has returned after treatment or hasn't responded to other therapies. Osteosarcoma is a type of bone cancer, and the study targets cases where the cancer can't be fully removed by surgery or has spread to the lungs. Suitable candidates for this trial have osteosarcoma that has recurred or isn't responding to treatment. Participants will take olaparib and ceralasertib in a 28-day cycle, with the possibility of continuing for up to two years if their condition remains stable. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important findings.

Do 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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain medications like potent CYP3A inhibitors or inducers, and there are specific washout periods for some treatments. It's best to discuss your current medications with the study team to ensure they don't interfere with the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of olaparib and ceralasertib has been tested for safety in patients with recurring osteosarcoma. Earlier studies used these drugs together to assess patient tolerance. Results indicated that while some side effects occurred, they were generally manageable.

Common side effects of olaparib and ceralasertib included nausea, tiredness, and some blood-related issues. However, most patients continued the treatment, suggesting these side effects were not severe for most.

Since this study is in a later phase, earlier research has already assessed the safety of these drugs. These studies suggest the treatment is relatively safe for humans, but being in a trial means unknown risks could still exist.

Overall, many patients seem to tolerate these drugs well. However, like any treatment, there is always some risk of side effects. Prospective participants should discuss potential risks and benefits with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Olaparib and Ceralasertib for treating recurrent osteosarcoma because it introduces a novel approach. Unlike current treatments like chemotherapy and surgery, Olaparib is a PARP inhibitor, which targets cancer cells by preventing them from repairing their DNA, leading to cell death. Ceralasertib, an ATR inhibitor, works by disrupting the cancer cells' ability to recover from DNA damage. This dual mechanism enhances the potential to effectively combat tumor growth in patients whose disease is difficult to remove surgically.

What evidence suggests that this trial's treatments could be effective for osteosarcoma?

Research has shown that combining the drugs olaparib and ceralasertib, which participants in this trial will receive, might help people with recurring osteosarcoma, a type of bone cancer. Studies have found that 40% of osteosarcoma patients have advanced cancer, which is hard to treat and has a low survival rate. In tests, some patients who took this drug combination had a 13.5% chance of not having their cancer worsen for four months. This treatment seems to work especially well for patients whose cancer no longer responds to other treatments. While these results are encouraging, more research is needed to fully understand how well this treatment works. ^{1 2 3 4 5}

Who Is on the Research Team?

Katherine A. Janeway

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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.

Participants in Cohort 1 must have measurable disease according to RECIST v1.1

Females must not be breast feeding

Exclusion Criteria

I have used drugs that affect liver enzymes CYP3A4 or CYP2B6.

I am not taking any strong CYP3A enzyme stimulators.

I do not have severe illnesses that could make treatment unsafe for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive olaparib and ceralasertib in 28-day cycles, up to 24 cycles

24 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are monitored for long-term outcomes such as overall survival

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Ceralasertib
• Olaparib

Trial Overview

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.

How Is the Trial Designed?

Group I: Olaparib-Ceralasertib Experimental Treatment 2 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.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Osteosarcoma Institute

Collaborator

Trials

2

Recruited

70+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Between 2017 and 2022, there was an increase in phase II trials for recurrent/refractory osteosarcoma, with 71 trials identified, indicating a growing interest in developing new treatments for this challenging condition.

Despite the increase in trials and a focus on targeted therapies, the overall efficacy data from 1361 patients showed disappointing results, highlighting the need for improved trial designs and a better understanding of the disease to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design? van Ewijk, R., Cleirec, M., Herold, N., et al.[2023]

The combination of osimertinib and platinum-based chemotherapy (OPP) demonstrated a high objective response rate of 90.9% in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer, indicating strong efficacy.

The treatment was well-tolerated, with no treatment-related deaths and an acceptable safety profile, as only 14.9% of patients discontinued due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Saito, R., Sugawara, S., Ko, R., et al.[2023]

In a study of 41 patients with advanced osteosarcoma, apatinib treatment showed potential adverse events, with the most common severe side effects being pneumothorax (16.22%) and wound dehiscence (10.81%).

Certain adverse events like hypertension and anorexia were associated with better outcomes, indicating they may serve as markers for clinical benefit in patients treated with apatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anorexia, Hypertension, Pneumothorax, and Hypothyroidism: Potential Signs of Improved Clinical Outcome Following Apatinib in Advanced Osteosarcoma. Xie, L., Xu, J., Sun, X., et al.[2022]

Osimertinib significantly improves progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, showing a median PFS of 10.1 months compared to 4.4 months with chemotherapy in a trial of 419 patients.

The safety profile of osimertinib is favorable compared to other EGFR tyrosine kinase inhibitors and chemotherapy, with common side effects including diarrhea and rash, making it a viable treatment option for patients who have progressed on previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. Odogwu, L., Mathieu, L., Goldberg, KB., et al.[2022]

In a study of 3578 patients with EGFR T790M-positive non-small cell lung cancer, osimertinib was associated with adverse drug reactions (ADRs) in 58.1% of patients, with serious interstitial lung disease occurring in 6.8% and leading to 0.8% overall mortality.

Despite the ADRs, osimertinib demonstrated significant efficacy, with a 69.9% objective response rate and a median progression-free survival of 12.3 months, supporting its benefit-risk profile in real-world use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan. Ohe, Y., Kato, T., Sakai, F., et al.[2022]

With complete surgical resection and multi-agent chemotherapy, up to 70% of patients with localized high-grade osteosarcomas can achieve long-term survival, highlighting the efficacy of current treatment strategies.

However, patients with nonresectable, primary metastatic, or relapsed osteosarcoma have a poor prognosis, indicating a need for novel therapeutic strategies to improve outcomes, as current treatments have not significantly changed in effectiveness over the past three decades.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel insights and therapeutic interventions for pediatric osteosarcoma. Kager, L., Tamamyan, G., Bielack, S.[2017]

Recent studies show that newer generation multi-Receptor Tyrosine Kinase (RTK) inhibitors, which target multiple pathways involved in osteosarcoma (OS) and Ewing sarcoma (ES), have demonstrated clinical efficacy in larger patient groups, although none have yet been approved for routine use.

Despite promising results, there is still uncertainty about which specific multi-RTK inhibitors are most effective for different patient subtypes, and treatment resistance remains a common challenge, highlighting the need for better-designed future trials to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma. Fleuren, EDG., Vlenterie, M., van der Graaf, WTA.[2023]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

In a study of 94 patients with advanced non-small-cell lung cancer (NSCLC) who had previously been treated, osimertinib showed a 47.3% overall objective response rate and a 90.1% disease control rate, indicating its effectiveness in this population.

Patients with the T790M mutation experienced significantly longer progression-free survival (PFS) compared to those without the mutation, highlighting osimertinib's targeted efficacy, especially in those with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. Mu, Y., Xing, P., Hao, X., et al.[2022]

The DUETTE trial is investigating the efficacy of combining ceralasertib, an ATR inhibitor, with olaparib, a PARP inhibitor, as a second maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, involving 192 participants.

The primary goal is to determine if this combination therapy can prolong progression-free survival compared to placebo, with the study also assessing tolerability and safety in patients who have previously received PARP inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. McMullen, M., Karakasis, K., Loembe, B., et al.[2021]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

In a study of 249 patients with second and subsequent recurrences of osteosarcoma, the five-year overall survival rates were notably low, ranging from 13% to 32% depending on the number of recurrences, highlighting the challenges in treating advanced osteosarcoma.

Achieving surgical remission significantly improved survival outcomes, with patients who underwent surgery showing better five-year survival rates compared to those who did not, emphasizing the critical role of surgical intervention in managing recurrent osteosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. Bielack, SS., Kempf-Bielack, B., Branscheid, D., et al.[2021]

Osteosarcoma (OS) treatment has improved overall survival rates to 60-75% with surgery and chemotherapy, but patients with pulmonary metastasis face a much lower 5-year survival rate of about 20%.

There is a pressing need for novel targeted therapies for relapsed and metastatic osteosarcoma, as current options are limited and often involve additional cytotoxic treatments, highlighting ongoing research efforts to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of TKI for Metastatic Osteogenic Sarcoma. Duffaud, F.[2021]

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