A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies

Conditions

• Advanced Solid Malignancies
• Colorectal Carcinoma (CRC)
• Metastatic Castrate-Resistant Prostate Carcinoma (mCRPC)
• Non-Small Cell Lung Cancer (NSCLC)

Eligibility Criteria

Sex

ALL

Age

18 Years - 130 Years

Healthy Volunteers

Not accepted

Interventions

• AZD4635 — DRUG
  AZD4635 will be administered orally as a nanosuspension or capsule on a continuous schedule in Arms A, B, C, D, E, F, G, H, I, J, K, KD, L, AA, and EA. The AZD4635 nanoparticle drug product will be constituted extemporaneously as an oral suspension by the patient immediately prior to dosing. In Arms CA, CB, and CC AZD4635 will be administered as 75 mg or 50 mg capsules. Additionally, in Arm CA, AZD4635 will also be administered at 150 mg and 200 mg, or a lower dose of 125 mg or 100 mg may be given.
• Durvalumab — DRUG
  Durvalumab will be administered by intravenous infusion once every 4 weeks. Durvalumab should be reconstituted using aseptic techniques with sterile water for injection. The reconstituted solution will be diluted with 0.9% (w/v) saline prior to IV infusion.
• 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.
• Oleclumab — DRUG
  Oleclumab 1500 mg will be given by IV infusion on Days 1 and 15 of each cycle.
• 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.

Study Details

This is a Phase 1, open-label, multicenter study of continuous oral dosing of AZD4635 administered to patients with advanced solid malignancies. Dosing will be escalated until a maximum-tolerated dose (MTD) is determined in patients. The MTD will be defined by dose-limiting toxicity. The study design allows an escalation of dose with intensive safety monitoring to ensure the safety of the patients. Expansion cohorts will further assess safety and preliminary anti-tumor activity in a variety of advanced solid tumor malignancies. Other dosing schedules and/or combinations may be evaluated based on the emerging PK and safety data. The primary objectives of this study are to: * Investigate the safety and tolerability of AZD4635 monotherapy when given orally (PO) to patients with advanced solid malignancies. * Investigate the safety, tolerability, and pharmacokinetics (PK) of AZD4635 monotherapy capsule formulation when given to patients with advanced solid malignancies. * Investigate the safety and tolerability of AZD4635 PO when given in combination with durvalumab, durvalumab plus oleclumab, or docetaxel to patients with advanced solid malignancies and to investigate the safety and tolerability of AZD4635 in combination with abiraterone acetate or enzalutamide in patients with mCRPC. * Define the maximum-tolerated dose (MTD) of AZD4635 in combination with durvalumab. * Define the recommended Phase 2 dose (RP2D) of AZD4635 in combination with abiraterone acetate or enzalutamide. * Determine the safety, tolerability, and immune effects of AZD4635 when administered in combination with durvalumab to patients with non-small cell lung cancer (NSCLC) who have previously received immunotherapy (Phase 1b portion). * Investigate the safety and tolerability of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy. * Define the RP2D of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy. * Investigate the safety and tolerability of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy. * Define the RP2D of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy.

Key Dates

Start date

Jun 17, 2016

Status verified

May 2023

Primary completion

Dec 31, 2020

Completion

Mar 31, 2023

Study Design

Enrollment

313 participants (actual)

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• Experimental: Arm A
  AZD4635 monotherapy as nanoparticle suspension 125 mg BID
• Experimental: Arm B
  AZD4635 monotherapy as nanoparticle suspension 75 mg QD
• Experimental: Arm C
  AZD4635 monotherapy as nanoparticle suspension 100 mg QD
• Experimental: Arm D
  AZD4635 as nanoparticle suspension 75 mg QD plus durvalumab
• Experimental: Arm E
  AZD4635 as nanoparticle suspension 100 mg QD plus durvalumab
• Experimental: Arm EA
  AZD4635 as nanoparticle suspension plus enzalutamide
• Experimental: Arm AA
  AZD4635 as nanoparticle suspension plus abiraterone acetate
• Experimental: Arm F
  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.
• Experimental: Arm G
  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.
• Experimental: Arm H
  AZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with other solid tumours.
• Experimental: Arm I
  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.
• Experimental: Arm J
  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.
• Experimental: Arm K
  AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with colorectal carcinoma.
• Experimental: Arm KD
  AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy-naïve patients with colorectal carcinoma.
• Experimental: Arm L
  AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with other solid tumours.
• Experimental: Arm CA
  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).
• Experimental: Arm CB
  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.
• Experimental: Arm CC
  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).

Primary Outcome Measure

The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 monotherapy orally. [ Time Frame: 3 weeks (One Cycle) ]

Locations (17)

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