AZD5335 for Cancer

(FONTANA Trial)

Recruiting at47 trial locations

Overseen by Funda Meric-Bernstam, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: AstraZeneca

Must not be taking: Corticosteroids, others

Disqualifiers: Brain metastases, Active infection, Cardiac issues, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment called AZD5335, which combines an antibody with a cancer-killing drug. It aims to see if this treatment is safe and effective for patients with advanced solid tumors. The antibody helps deliver the drug directly to the cancer cells, potentially reducing harm to healthy cells.

Do I need to stop my current medications to join the trial?

The trial information does not clearly specify if you need to stop your current medications. However, it mentions that treatment with certain medications requires adequate 'washout periods' (time without taking certain medications) before starting the study treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug AZD5335 for cancer?

Research shows that AZD5305, a component of AZD5335, is better tolerated than earlier similar drugs and led to a partial response in 25% of patients with certain genetic mutations in a trial. Additionally, combining a similar drug with another treatment improved effectiveness in preclinical studies, suggesting potential benefits for AZD5335. ^{1 2 3 4 5}

Is AZD5335 safe for humans?

AZD5335, also known as AZD5305, is generally well-tolerated in patients with certain types of cancer, showing better tolerance compared to earlier similar drugs. ^{1 3 6 7 8}

How is the drug AZD5335 different from other cancer treatments?

AZD5335, also known as Saruparib, is a next-generation, highly selective PARP1 inhibitor that is more tolerable than earlier PARP inhibitors, making it a potentially better option for patients with certain genetic mutations in cancers like ovarian and breast cancer. ^{1 3 8 9 10}

Research Team

Funda Meric-Bernstam, MD

Principal Investigator

UT MD Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced solid tumors who have tried other treatments or consider a clinical trial their best option. They must be able to consent, provide tumor samples, and have an ECOG status of 0 or 1 (fully active or restricted in physically strenuous activity but ambulatory). Exclusions include patients with certain lung conditions, infections like TB/HIV/HBV/HCV, unresolved toxicities from past therapies, brain metastases requiring steroids, serious heart issues within the last year, pregnancy/breastfeeding intentions during the study period.

Inclusion Criteria

Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol

Willing to provide archival or baseline tumor sample

Participants must have a disease that can be measured using specific guidelines.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

Patients with a known hypersensitivity to study intervention or any of the excipients of the product

Previous enrolment in the present study. **Other module specific criteria may apply

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD5335 as monotherapy or in combination with other anti-cancer agents

12 weeks

Predefined intervals throughout the treatment period

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• AZD5305 (Antibody-drug conjugate)
• AZD5335 (Antibody-drug conjugate)

Trial Overview The study tests AZD5335 alone or combined with other anti-cancer agents in participants with solid tumors. It aims to assess safety and cancer-fighting ability. The phase I/IIa design will first determine safe dosages and then evaluate how well the treatment works.

Participant Groups

Group I: Module 4: AZD5335 + Carboplatin +/- Bevacizumab Experimental Treatment 2 Interventions

AZD5335 + Carboplatin +/- Bevacizumab

Group II: Module 3: AZD5335 + Bevacizumab Experimental Treatment 1 Intervention

AZD5335 + Bevacizumab

Group III: Module 2: AZD5335 + Saruparib Experimental Treatment 2 Interventions

AZD5335 + Saruparib

Group IV: Module 1: AZD5335 Monotherapy Experimental Treatment 1 Intervention

AZD5335 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]

AZD0156 is a selective inhibitor of the ATM protein that enhances the effectiveness of radiation therapy by blocking ATM signaling, leading to increased tumor growth inhibition in preclinical models.

When combined with the PARP inhibitor olaparib, AZD0156 significantly impairs DNA repair in cancer cells, resulting in increased cell death and improved treatment outcomes in various cancer types, including triple-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically. Riches, LC., Trinidad, AG., Hughes, G., et al.[2020]

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]

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]

The recommended phase II dose (RP2D) of AZD8931 combined with chemotherapy (Xelox) was determined to be 20 mg twice daily, showing an acceptable safety profile despite some dose-limiting toxicities observed in 24 patients, including skin rash and severe gastrointestinal side effects.

In the expansion phase, the combination of Xelox and AZD8931 resulted in a lower complete resection rate (45%) compared to Xelox alone (90%), and while the six-month progression-free survival was 85% for the combination group, it was 100% for the Xelox-only group, indicating that AZD8931 may not enhance surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma. Thomas, A., Virdee, PS., Eatock, M., et al.[2023]

AZD5438, a new cyclin-dependent kinase inhibitor, was tested in a first-in-man study with 23 healthy male volunteers, revealing a maximum tolerated dose of 80 mg and a well-tolerated dose of 60 mg, which caused mild nausea but no vomiting.

The pharmacokinetic profile showed that AZD5438 has a short plasma half-life of 1-3 hours and is primarily cleared through metabolism, with less than 1% excreted unchanged in urine, guiding future studies on its pharmacodynamic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers. Camidge, DR., Smethurst, D., Growcott, J., et al.[2021]

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]

AZD1775, a WEE1 kinase inhibitor, was found to be safe and well-tolerated in a study involving 202 patients with refractory solid tumors, both as a monotherapy and in combination with chemotherapy.

The study showed that AZD1775 effectively engaged its target, leading to a 21% response rate in TP53-mutated patients, compared to 12% in those with wild-type TP53, suggesting it may be particularly beneficial for patients with TP53 deficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. Leijen, S., van Geel, RM., Pavlick, AC., et al.[2023]

AZD5363, an oral pan-AKT inhibitor, was found to be well tolerated in a phase I study involving 110 patients with advanced solid tumors, with a recommended phase II dose of 480 mg showing manageable side effects like diarrhea and hyperglycemia.

In patients with PIK3CA-mutant breast and gynecologic cancers, AZD5363 demonstrated preliminary clinical activity, with 46% and 56% of patients experiencing a reduction in tumor size, although the response rates did not meet the predefined threshold for further recruitment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers. Banerji, U., Dean, EJ., Pérez-Fidalgo, JA., et al.[2022]

AZD5363 is a potent inhibitor of AKT, effectively reducing tumor cell proliferation in various cancer types, particularly in breast cancer, with a significant relationship between genetic mutations (PIK3CA and PTEN) and sensitivity to the drug.

In animal studies, AZD5363 demonstrated dose-dependent tumor growth inhibition and enhanced the effectiveness of other cancer treatments, suggesting its potential as a monotherapy or in combination therapies for personalized cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Davies, BR., Greenwood, H., Dudley, P., et al.[2022]

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

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

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

4. 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]

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

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma. [2023]

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

A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers. [2021]

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

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

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

Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. [2023]

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

A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers. [2022]

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

Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. [2022]