AZD5305 for Advanced Cancers

(PETRA Trial)

Recruiting at 54 trial locations

Overseen By AstraZeneca Breast Cancer Study Locator Service

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: AstraZeneca

Must not be taking: CYP3A4 inhibitors, QT drugs

Disqualifiers: Cardiac conditions, Brain metastases, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called AZD5305, which blocks a protein that helps cancer cells repair their DNA. It aims to see if the drug is safe and effective for patients with advanced solid tumors. By stopping the repair process, the drug hopes to kill cancer cells. AZD5305 has shown better tolerance in patients compared to earlier similar drugs.

Will I have to stop taking my current medications?

The trial requires stopping certain medications, such as those that strongly affect liver enzymes (CYP3A4 inhibitors or inducers) and drugs that affect heart rhythms. You should discuss your current medications with the trial team to see if any need to be stopped.

What data supports the effectiveness of the drug AZD5305 for advanced cancers?

Research shows that AZD5305, a new type of drug called a PARP1 inhibitor, is better tolerated than older drugs in its class for certain cancers like ovarian and breast cancer. In a study, 25% of patients had a partial response, meaning their cancer shrank. ^{1 2 3 4 5}

Is AZD5305 safe for use in humans?

AZD5305, a next-generation PARP1 inhibitor, has been found to be more tolerable than earlier PARP inhibitors in patients with certain types of cancer, such as ovarian and breast cancer, indicating it is generally safe for human use. ^{1 4 6 7 8}

Research Team

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults over 18 with advanced solid tumors suitable for the study, who have not had certain treatments like strong CYP3A4 inhibitors or inducers, recent major surgery, or live vaccines. They should have a life expectancy of at least 12 weeks and an ECOG performance status of 0-2.

Inclusion Criteria

My organs and bone marrow are working well.

I am 18 years old or older.

My advanced cancer is confirmed and deemed suitable for this study.

Exclusion Criteria

My heart condition meets the study's requirements.

I haven't taken any experimental drugs recently.

I have had severe low blood counts for more than 2 weeks.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD5305 as monotherapy or in combination with anti-cancer agents

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

40 days

Long-term follow-up

Participants are monitored for progression-free survival and other long-term outcomes

1 year

Treatment Details

Interventions

• AZD5305 (PARP Inhibitor)
• Carboplatin (Chemotherapy)
• Dato-DXd (Antibody-Drug Conjugate)
• Paclitaxel (Chemotherapy)
• T-Dxd (Antibody-Drug Conjugate)

Trial Overview The trial is testing AZD5305 alone or combined with other anti-cancer drugs to see if it's safe and effective against various advanced cancers. It involves patients who may/may not have had previous PARPi-based therapy depending on the part of the study they're in.

Participant Groups

Group I: Module 6 AZD5305 + Camizestrant Experimental Treatment 2 Interventions

AZD5305 + Camizestrant

Group II: Module 5 AZD5305 + Datopotamab Deruxtecan Experimental Treatment 2 Interventions

AZD5305 + Dato-DXd

Group III: Module 4: AZD5305 + Trastuzumab Deruxtecan Experimental Treatment 2 Interventions

AZD5305 + T- DXd

Group IV: Module 3: AZD5305 + Carboplatin with or without Paclitaxel Experimental Treatment 3 Interventions

AZD5305 + Carboplatin with or without Paclitaxel

Group V: Module 2: AZD5305 + Paclitaxel Experimental Treatment 2 Interventions

AZD5305 + Paclitaxel

Group VI: Module 1: AZD5305 Monotherapy Experimental Treatment 1 Intervention

AZD5305 Monotherapy

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

AZD5305, a new PARP1 inhibitor, is better tolerated than older PARP inhibitors in patients with specific cancer types and genetic mutations, including ovarian, HER2-negative breast, pancreatic, and prostate cancers.

In a phase I/IIa trial involving 40 patients, 25% showed a partial response to treatment, indicating promising efficacy for this next-generation drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AZD5305 More Tolerable than Earlier PARP Agents. [2022]

In a phase I study involving 21 patients with advanced solid tumors, the combination of olaparib and topotecan was found to have a maximum tolerated dose (MTD) of topotecan 1.0 mg/m²/day for 3 days plus olaparib 100 mg twice daily, primarily due to dose-limiting toxicities like neutropenia and thrombocytopenia.

The study highlighted that while the combination treatment was associated with common adverse events such as fatigue and gastrointestinal issues, the significant hematological side effects led to the decision not to pursue further development of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Samol, J., Ranson, M., Scott, E., et al.[2022]

In the phase 3 JAVELIN Renal 101 trial involving 886 treatment-naive patients with advanced renal cell carcinoma, the combination of avelumab and axitinib significantly improved progression-free survival (PFS) compared to sunitinib, with a median PFS of 13.8 months versus 7.0 months for the PD-L1+ population.

While overall survival (OS) data were still immature, the results suggest that avelumab plus axitinib may offer a promising treatment option for patients with advanced renal cell carcinoma, particularly those with PD-L1+ tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Choueiri, TK., Motzer, RJ., Rini, BI., et al.[2022]

A phase II study of the PARP inhibitor olaparib confirmed its clinical benefits for cancer patients with inherited BRCA1 and BRCA2 mutations, particularly in advanced breast and ovarian cancers.

The study also provided evidence that olaparib is effective against pancreatic and prostate cancers, expanding its potential use in treating various cancer types associated with these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib shows promise in multiple tumor types. [2014]

The combination of erlotinib (an EGFR inhibitor) and olaparib (a PARP inhibitor) significantly enhances antitumor effects in ovarian cancer models compared to either drug alone, indicating a promising new treatment strategy.

The study found that this combination therapy works by reducing key signaling pathways (ERK1/2 and AKT) and enhancing autophagy, which may help overcome resistance to conventional therapies in advanced ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy. Sui, H., Shi, C., Yan, Z., et al.[2018]

AZD5363, an oral medication for advanced solid tumors, showed a more tolerable safety profile with intermittent dosing compared to continuous dosing, leading to a recommended dose of 480 mg twice daily on a 4 days on, 3 days off schedule.

Preliminary results indicated antitumor activity, particularly in patients with the Akt1 (E17K) mutation, suggesting that this mutation may help predict which patients are more likely to respond to AZD5363 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. Tamura, K., Hashimoto, J., Tanabe, Y., et al.[2019]

AZD4635, a potential anticancer therapy, showed comparable oral bioavailability between its nanosuspension and capsule forms, but a high-fat meal significantly reduced the rate of absorption, delaying peak concentration by over 2 hours without affecting the overall extent of absorption.

Co-administration with fluvoxamine resulted in a substantial increase in AZD4635 exposure, particularly in smokers, indicating that drug interactions can significantly enhance its pharmacokinetics, while all treatment regimens were well tolerated with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations. Moorthy, G., Pouliot, GP., Graham, L., et al.[2023]

AZD1775, a Wee1 inhibitor, demonstrated good penetration into brain tumors in patients with recurrent glioblastoma, achieving a median unbound tumor-to-plasma concentration ratio of 3.2, which suggests effective delivery of the drug to the tumor site.

The study provided evidence of clinical biological activity in glioblastoma, as indicated by the suppression of the Wee1 pathway and increased DNA damage, with no reported drug-related adverse events, highlighting its potential as a safe treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients. Sanai, N., Li, J., Boerner, J., et al.[2020]

References

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

AZD5305 More Tolerable than Earlier PARP Agents. [2022]

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

Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. [2022]

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

Olaparib shows promise in multiple tumor types. [2014]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy. [2018]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations. [2023]

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

Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients. [2020]