Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
AZD4635 · 4 trials · 7 indications
rPFS was defined as the time from first dose to radiographic progression, assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 (Prostate Cancer Working Group 3) criteria \[bone\] or death from any cause, whichever occurred first.
The confirmed objective response is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines, assessed by computed tomography (CT) scan/ magnetic resonance imaging (MRI) scan/ positron emission tomography (PET) scan and bone scan. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between.
A confirmed PSA response is defined as reduction in the PSA level of \>= 50% from baseline to the lowest post-baseline PSA results, measured twice, at least 3 weeks apart by the PCWG3 criteria.
Investigate the safety and tolerability of AZD4635
Investigate the safety and tolerability of AZD4635
A Bayesian Logistic Regression Model (BLRM) based approach will be used to identify the set of AZD4635 doses where the incidence of DLTs is no larger than 33%. In each arm, up to 3 patients will be initially assessed. The dose will be escalated to the next higher dose level if all 3 patients in the previous dose level complete the DLT evaluation period without a DLT. Following the first DLT, the BLRM model will be run and the output made available to the safety review committee (SRC) to guide further dosing decisions. Each dose cohort will include a maximum of 6 patients.
A Bayesian Logistic Regression Model (BLRM) based approach will be used to identify the set of AZD4635 doses where the incidence of DLTs is no larger than 33%. In each arm, up to 3 patients will be initially assessed. The dose will be escalated to the next higher dose level if all 3 patients in the previous dose level complete the DLT evaluation period without a DLT. Following the first DLT, the BLRM model will be run and the output made available to the safety review committee (SRC) to guide further dosing decisions. Each dose cohort will include a maximum of 6 patients.
The starting dose of AZD4635 is 50 mg PO QD. Escalations of AZD4635 will be made based on emerging data, including nonclinical or clinical evidence, and assessment by the Safety Review Committee (SRC). Each dose cohort will include a maximum of 6 evaluable patients. An additional 6 patients will be treated at selected dose(s) to obtain further the safety, tolerability, and PK.
Safety and tolerability will be assessed in monotherapy and combination cohorts by determining the incidence of adverse events, including abnormal laboratory results, physical examination findings, vital signs, and urinalysis.
| Arm | Type | Description |
|---|---|---|
| Arm A: AZD4635 + durvalumab | EXPERIMENTAL | AZD4635 plus durvalumab (Arm A) will consist of participants with mCRPC previously treated with one or more approved NHAs (eg, abiraterone acetate, enzalutamide, apalutamide and/or darolutamide), and one or more taxanes, or participants who are taxane ineligible. |
| Arm B: AZD4635 + durvalumab + cabazitaxel | EXPERIMENTAL | AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of participants with mCRPC previously treated with docetaxel and one prior NHA (either abiraterone acetate or enzalutamide but not both (prior apalutamide is not allowed in Arm B). |
| Module 1 (AZD4635 75 mg + Durvalumab 1500 mg) | EXPERIMENTAL | Participants will receive monotherapy of AZD4635 75 mg orally once daily (QD) for first 14 days and thereafter will continue to receive 75 mg orally QD in combination with durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W) until will derive clinical benefit as judged by the investigator, confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first. |
| Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg) | EXPERIMENTAL | Participants will receive combination therapy of AZD4635 (50 mg / 75 mg orally QD) and oleclumab 1500 mg IV (every 2 weeks of 28-day cycle for the first 4 doses and Q4W thereafter) until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first. |
| AZD4635 monotherapy | EXPERIMENTAL | Dose escalation of AZD4635 monotherapy for patients with advanced solid malignancies |
| Arm A | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension 125 mg BID |
| Arm B | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension 75 mg QD |
| Arm C | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension 100 mg QD |
| Arm D | EXPERIMENTAL | AZD4635 as nanoparticle suspension 75 mg QD plus durvalumab |
| Arm E | EXPERIMENTAL | AZD4635 as nanoparticle suspension 100 mg QD plus durvalumab |
| Arm EA | EXPERIMENTAL | AZD4635 as nanoparticle suspension plus enzalutamide |
| Arm AA | EXPERIMENTAL | AZD4635 as nanoparticle suspension plus abiraterone acetate |
| Arm F | EXPERIMENTAL | AZD4635 as nanoparticle suspension plus durvaluamb in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G. |
| Arm G | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G. |
| Arm H | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with other solid tumours. |
| Arm I | EXPERIMENTAL | AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J. |
| Arm J | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J. |
| Arm K | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with colorectal carcinoma. |
| Arm KD | EXPERIMENTAL | AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy-naïve patients with colorectal carcinoma. |
| Arm L | EXPERIMENTAL | AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with other solid tumours. |
| Arm CA | EXPERIMENTAL | AZD4635 capsule formulation monotherapy 75 mg, 150 mg, and 200 mg QD. A lower dose of 125 mg or 100 mg may be given. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CA. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycle 1 and Cycle 2 will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, and 6). |
| Arm CB | EXPERIMENTAL | AZD4635 capsule formulation 50 mg QD or 75 mg QD plus durvalumab and oleclumab. The pharmacokinetics of AZD4635 capsule formulation will be characterized on Cycle 1, 2, and 4 (Day 1) in Arm CB. Steady-state pharmacokinetics will be assessed on Cycle 2 Day 15. Cycle 1 will be administered in a 3-week cycle to assess the safety and dose-limiting toxicity (DLT). PKs will also be collected on Day 1 of Cycles 3 and 5. |
| Arm CC | EXPERIMENTAL | AZD4635 capsule formulation 50 mg QD or 75 mg QD plus docetaxel. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CC. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycles will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, and 6). |
| Name | Type | Description |
|---|---|---|
| AZD4635 | DRUG | Subjects will receive AZD4635 orally daily |
| Durvalumab | DRUG | Subjects will receive intravenous durvalumab every 4 weeks for Arm A and every 3 weeks for Arm B. |
| Cabazitaxel | DRUG | Subjects will receive intravenous cabazitaxel every 3 weeks |
| Oleclumab | DRUG | In Module 2, participants will receive oleclumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q2W of 28-day cycle for the first 4 doses and Q4W thereafter until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first. |
| Abiraterone Acetate | DRUG | Abiraterone acetate 1000 mg PO QD will be given with prednisone BID. The patient must receive abiraterone/prednisone according to the prescribing information during the DLT assessment period, Cycle 1 and Cycle 2. After Cycle 2 necessary abiraterone/ prednisone dose modifications may follow institutional standard practice. Abiraterone acetate is supplied in 250 mg tablets. |
| Enzalutamide | DRUG | Enzalutamide 160 mg PO QD will be dosed per the approved package insert. The patient must receive enzalutamide according to the prescribing information during the DLT assessment period, Cycle 1 and Cycle 2. After Cycle 2 necessary enzalutamide dose modifications may follow institutional standard practice. Enzalutamide is supplied as 40 mg soft gelatin capsules. |
| Docetaxel | DRUG | Patients in Cohort CC will receive docetaxel 75 mg/m² by IV infusion according to institutional standards of practice on Day 1 of each treatment cycle. If a patient's body surface area is greater than 2.2 m², the docetaxel dose will be adjusted to a body surface area of 2.2 m². The patient should be pre-medicated with oral dexamethasone 8 mg (or equivalent) twice daily starting the day prior to treatment for a total of 3 days, or according to institutional standards of practice. |
Inclusion Criteria: 1. Histologically confirmed adenocarcinoma of the prostate. 2. Known castrate-resistant disease. 3. Evidence of disease progression ≤6 months. 4. Body weight \>30 kg at screening. 5. Willingness to adhere to the study treatment-specific contraception requirements. 6. Adequate bo...
AZD4635 is an investigational small molecule being studied in oncology for advanced solid malignancies, including progressive metastatic castrate-resistant prostate cancer and prostate cancer. It has been evaluated in clinical trials in patients with mCRPC, non-small cell lung cancer, and colorectal carcinoma. It is not an approved therapy.
AZD4635 is developed by AstraZeneca PLC, which trades on the Nasdaq under the ticker AZN. AstraZeneca sponsored the clinical studies of AZD4635 in advanced solid malignancies and prostate cancer, including the Phase 1 and Phase 2 trials listed on ClinicalTrials.gov.
AZD4635 has been studied in Phase 1 and Phase 2 clinical trials. The program includes a Phase 1 study in advanced solid malignancies and Phase 2 studies in prostate cancer and metastatic castrate-resistant prostate cancer. All listed trials are completed, and AZD4635 is investigational rather than approved.
AZD4635 has been evaluated in completed trials including NCT02740985, a Phase 1 study in advanced solid malignancies with 313 patients, and NCT03980821, a Phase 1 study in Japanese patients. Phase 2 trials include NCT04495179 in mCRPC with durvalumab and cabazitaxel, and NCT04089553 in prostate cancer.
Across the listed clinical trials, 323 patients have been enrolled in studies of AZD4635. The largest was NCT02740985 with 313 participants, followed by NCT04089553 with 59, NCT04495179 with 30, and NCT03980821 with 10. Enrollment figures reflect the individual trial protocols.
AZD4635 is not approved and remains an investigational agent in clinical development. It has completed Phase 1 and Phase 2 trials in advanced solid malignancies and prostate cancer, but no regulatory approval has been granted for any indication based on the available development information.