Combination Therapy with Cediranib, Olaparib, and Durvalumab for Advanced Solid Tumors

(DAPPER Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Other malignancy, CNS metastases, 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: Unknown

Duration: 3 years

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of medicines to help the immune system fight advanced colorectal, pancreatic, and soft tissue cancers. It aims to see if these new treatments can be more effective for patients whose cancers are hard to treat with standard therapies.

Will I have to stop taking my current medications?

The trial requires a 4-week period without any prior anti-cancer treatments before starting the study. Additionally, if you are taking certain medications that strongly affect liver enzymes (CYP3A inhibitors or inducers), you may need to stop them 1-5 weeks before starting the trial, depending on the specific medication.

What data supports the effectiveness of the drug combination of Cediranib, Olaparib, and Durvalumab for advanced solid tumors?

Research shows that the combination of Cediranib and Olaparib increased progression-free survival (the time during which the cancer does not get worse) in women with recurrent ovarian cancer. Additionally, the combination of Durvalumab with either Olaparib or Cediranib showed promising disease control rates in women's cancers, with some patients experiencing partial responses and stable disease. ^{1 2 3 4 5}

Is the combination of Cediranib, Olaparib, and Durvalumab safe for humans?

The combination of Cediranib, Olaparib, and Durvalumab has been studied for safety in women with recurrent cancers. No dose-limiting toxicities were found with Durvalumab plus Olaparib, but some adverse events like high blood pressure and fatigue were noted with Cediranib. Overall, the combinations were considered tolerable. ^{1 2 4 6 7}

What makes the combination therapy with Cediranib, Olaparib, and Durvalumab unique for treating advanced solid tumors?

This combination therapy is unique because it combines three different mechanisms: Cediranib reduces blood vessel growth to tumors, Olaparib increases DNA damage in cancer cells, and Durvalumab boosts the immune system's ability to fight cancer. This multi-faceted approach aims to enhance the overall anti-tumor activity compared to using these drugs individually. ^{1 2 3 4 6}

Research Team

Lillian Siu, MD

Principal Investigator

Princess Margaret Cancer Centre

Eligibility Criteria

Adults with advanced colorectal cancer, pancreatic adenocarcinoma, or leiomyosarcoma that's not curable and has failed standard therapy can join. They must be willing to use effective contraception, provide tumor tissue samples, have normal organ function, and no recent major surgeries. Excluded are those with certain heart conditions, uncontrolled hypertension or seizures, recent bleeding events or blood transfusions.

Inclusion Criteria

Females of childbearing potential who are sexually active with a non-sterilized male partner must agree to practice true abstinence or at least two effective methods of contraception from 28 days prior to starting durvalumab, olaparib or cediranib, and agree to continue using such precautions while taking durvalumab, olaparib or cediranib and for 90 days following the last dose of investigational product(s). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. They must also refrain from egg cell donation and breastfeeding during study participation and for at least 90 days after the final dose of investigational product(s)

Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use at least two effective methods of contraception from Day 1 through 90 days after receipt of the final dose of investigational product(s). In addition, they must refrain from sperm donation for 90 days after the final dose of investigational product(s). Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential

Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

Exclusion Criteria

Only supratentorial metastases allowed

No history of intracranial hemorrhage

Measurable disease outside the CNS

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab intravenously every 4 weeks. Cohort A receives olaparib orally twice a day continuously, while Cohort B receives cediranib orally once a day for 5 consecutive days with 2 days off each week.

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including overall response rate, clinical benefit rate, progression-free survival, and overall survival.

3 years

Treatment Details

Interventions

• Cediranib
• Durvalumab
• Olaparib

Trial Overview The trial tests combinations of Olaparib (a pill for DNA repair inhibition), Cediranib (a pill for blocking blood vessel growth in tumors), and Durvalumab (an IV drug boosting immune response against cancer). Participants will receive treatments based on their assigned cohort to see how these drugs affect tumor biomarkers.

Participant Groups

Group I: Cohort B Experimental Treatment 2 Interventions

Cediranib (given orally at a dose of 20 mg daily, 5 days on 2 days off) in combination with Durvalumab (given intravenously at a dose of 1500 mg every 4 weeks)

Group II: Cohort A Experimental Treatment 2 Interventions

Olaparib (given orally at a dose of 300 mg twice a day) in combination with Durvalumab (given intravenously at a dose of 1500 mg every 4 weeks)

Cediranib is already approved in United States, European Union for the following indications:

Approved in United States as Cediranib for:

• Alveolar soft part sarcoma

Approved in European Union as Cediranib for:

• Alveolar soft part sarcoma

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

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

Findings from Research

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

The combination of olaparib, cediranib, and durvalumab was found to be tolerable in a phase 1 study involving 9 patients with recurrent women's cancers, with no dose-limiting toxicities reported.

The treatment showed promising preliminary efficacy, with a 67% clinical benefit rate, including partial responses in 44% of patients, indicating potential for further investigation in a phase 2 study for recurrent ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Zimmer, AS., Nichols, E., Cimino-Mathews, A., et al.[2023]

In a phase I study involving 26 women with recurrent cancers, the combination of the PD-L1 inhibitor durvalumab with olaparib or cediranib was found to be tolerable and showed promising anti-tumor activity, with an 83% disease control rate for the durvalumab plus olaparib group.

The recommended phase II doses were established as durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice daily, or cediranib 20 mg on an intermittent schedule, indicating that these combinations could be viable options for further investigation in treating recurrent women's cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Lee, JM., Cimino-Mathews, A., Peer, CJ., et al.[2022]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

In a phase IIb trial involving 60 women with platinum-resistant recurrent ovarian cancer, the combination of cediranib and olaparib showed a modest objective response rate (ORR) of 15.3%, indicating some clinical activity in this heavily pretreated population.

The treatment was associated with significant safety concerns, as 73.3% of patients experienced grade ≥3 adverse events, highlighting the need for careful monitoring and further research into biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. Lee, JM., Moore, RG., Ghamande, S., et al.[2023]

The maximum-tolerated dose (MTD) of cediranib in children with recurrent CNS tumors was initially set at 32 mg/m²/day, but excessive toxicities led to concerns about its long-term tolerability.

At a lower dose of 20 mg/m²/day, cediranib still showed poor tolerability, indicating that both doses may not be suitable for extended treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial and PK study of cediranib (AZD2171), an orally bioavailable pan-VEGFR inhibitor, in children with recurrent or refractory primary CNS tumors. Kieran, MW., Chi, S., Goldman, S., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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]

3. United States pubmed.ncbi.nlm.nih.gov

Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). [2015]

4. United States pubmed.ncbi.nlm.nih.gov

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]

5. England pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

A phase I trial and PK study of cediranib (AZD2171), an orally bioavailable pan-VEGFR inhibitor, in children with recurrent or refractory primary CNS tumors. [2018]