Olaparib + Durvalumab for Solid Tumors (SOLID Trial)
Recruiting in Palo Alto (17 mi)
Overseen ByEric Chen, M.D.
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University Health Network, Toronto
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a phase 2 study of the combination of drugs olaparib and durvalumab for the treatment of isocitrate dehydrogenase or (IDH) mutated solid tumors. The purpose of this study is to assess the efficacy of the drug combination via overall response rate and overall disease control rate.
It is believed that giving olaparib and durvalumab together would be more useful when given to patients with IDH-mutated solid tumors than giving each drug alone.
What makes the drug combination of Olaparib and Durvalumab unique for treating solid tumors?
The combination of Olaparib, a PARP inhibitor that targets cancer cells with DNA repair issues, and Durvalumab, an immunotherapy drug that helps the immune system attack cancer cells, is unique because it combines two different mechanisms to enhance anti-tumor activity, potentially offering a more effective treatment for certain solid tumors compared to standard therapies.
15679Is the combination of Olaparib and Durvalumab safe for humans?
Studies have shown that the combination of Olaparib and Durvalumab is generally safe, with no dose-limiting toxicities reported. Some side effects like fatigue and high blood pressure were noted, but the treatment was considered tolerable.
246910Will I have to stop taking my current medications?
The trial requires a washout period (time without taking certain medications) for known strong or moderate CYP3A inducers before starting olaparib, which is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. This does not apply to patients in Cohort A. If you are taking these medications, you may need to stop them before joining the trial.
What data supports the effectiveness of the drug combination of olaparib and durvalumab for solid tumors?
Research shows that the combination of olaparib and durvalumab has shown antitumor activity in preclinical studies and increased response rates in breast cancer treatment. Additionally, durvalumab alone has demonstrated effectiveness in treating various solid tumors, including non-small-cell lung cancer.
346810Eligibility Criteria
Adults with IDH-mutated solid tumors, including specific brain and bile duct cancers, who have undergone limited prior treatments can join this trial. They must be in good physical condition (ECOG 0-1), not pregnant, willing to prevent pregnancy, and able to swallow pills. Participants should have a life expectancy of at least 16 weeks and stable health without recent major surgeries or uncontrolled medical issues.Inclusion Criteria
My brain tumor is IDH mutant and I've had no more than 2 treatments after it first came back.
I am 18 years old or older.
I am fully active or can carry out light work.
I have IDH mutant adenocarcinoma of the biliary tract and have had 2 or fewer treatments for advanced disease.
My brain tumor is IDH mutant and I've had no more than 2 treatments after it first came back.
I am willing and able to follow the study's treatment and visit schedule.
My body weight is over 30 kg.
My disease can be measured or tracked.
I have IDH mutant adenocarcinoma of the biliary tract and have had 2 or fewer treatments for advanced disease.
I am 18 years old or older.
I am fully active or can carry out light work.
Exclusion Criteria
I do not have any serious, uncontrolled health issues or infections.
I have lasting side effects from cancer treatment, but not hair loss or blood test issues.
I cannot swallow pills or have stomach issues affecting medication absorption.
I had major surgery over 2 weeks ago and have recovered from it.
I have received an organ transplant from another person.
I have had an autoimmune or inflammatory disorder in the past 2 years.
My heart's electrical activity is abnormal, or I have a family history of long QT syndrome.
I have been diagnosed with myelodysplastic syndrome or acute myeloid leukemia.
I have brain metastases that are not under control and cause symptoms.
I do not have any active infections, including tuberculosis.
I have never been treated with PARP or PD-1/PD-L1 inhibitors like olaparib or durvalumab.
I am not pregnant, breastfeeding, nor plan to become pregnant during the study.
I haven't had chemotherapy or radiotherapy (except for comfort care) in the last 4 weeks.
I have active hepatitis B or C.
Participant Groups
The study is testing the combination of two drugs: Olaparib and Durvalumab for treating IDH-mutated solid tumors. The goal is to see if taking these drugs together works better than when they're taken separately by measuring how well the cancer responds and how long patients' diseases are controlled.
2Treatment groups
Experimental Treatment
Group I: Cohort B: IDH mutated cholangiocarcinomaExperimental Treatment2 Interventions
Olaparib, by mouth (orally), twice a day, every day. Durvalumab, by vein (intravenously), on Day 1 of every 28 day cycle.
Group II: Cohort A: IDH mutated gliomaExperimental Treatment2 Interventions
Olaparib, by mouth (orally), twice a day, every day. Durvalumab, by vein (intravenously), on Day 1 of every 28 day cycle.
Durvalumab is already approved in European Union, United States, Japan for the following indications:
🇪🇺 Approved in European Union as Imfinzi for:
- Locally advanced, unresectable non-small cell lung cancer (NSCLC)
🇺🇸 Approved in United States as Imfinzi for:
- Extensive-stage small cell lung cancer (ES-SCLC)
- Limited-stage small cell lung cancer (LS-SCLC)
- Locally advanced or metastatic urothelial carcinoma
🇯🇵 Approved in Japan as Imfinzi for:
- Not specified in provided sources
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Princess Margaret Cancer CentreToronto, Canada
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Who is running the clinical trial?
University Health Network, TorontoLead Sponsor
References
Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. [2023]Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab.
Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. [2022]Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.
Durvalumab in non-small-cell lung cancer patients: current developments. [2018]Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy. Impressive activity has been recently reported after chemoradiation in locally advanced patients; promising activity was observed with other ICI combinations, and potentially with other drugs including platinum-based chemotherapy. In contrast, early data reveal lower response rates in EGFR and ALK-positive patients.
Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.
A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses. [2023]Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable.
Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. [2021]Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.
Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. [2023]The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.
I-SPY2 platform: New lessons from the olaparib and durvalumab combination in breast cancer treatment. [2021]I-SPY2 platform-based phase II studies in breast cancer might speed up the development of new treatments. In this issue of Cancer Cell, Pusztai et al. report that adding durvalumab and olaparib to standard neoadjuvant chemotherapy significantly increases the pathological complete response rate in patients with HER2-negative breast cancer irrespective of the hormone receptor status.
New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]Olaparib (Lynparza) is now approved for the adjuvant treatment of adult patients who have, or are suspected to have, the germline variation of BRCA-mutated human epidermal growth factor receptor 2-negative high-risk early breast cancer and who were previously treated with neoadjuvant or adjuvant chemotherapy.
A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations. [2023]To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects.