Last updated on June 2020

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


Brief description of study

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.

Detailed Study Description

The study will be conducted in two segments. The first segment of the study, designated Phase 1a, will be a dose escalation design in order to assess the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of ascending doses of AZD4635 as monotherapy, in combination with durvalumab or durvalumab plus oleclumab, in combination with docetaxel, and in combination with either abiraterone acetate or with enzalutamide.

A capsule formulation of AZD4635 will be evaluated in 3 arms (arms CA, CB, and CC). An oral nanoparticle suspension in water constituted extemporaneously by the patient will be administered in all other treatment arms. Most patients who started therapy with the nanoparticle suspension will transition to the capsule dosage form depending on the arm they are assigned to and emerging data. Active patients in arms C, D, E, F, G, H, I, J, K, KD, and L should be offered the option to transition to the capsule formulation at the discretion of the Investigator in discussion with the Medical Monitor. Patients in study arms AA and AE receiving AZD4635 as the nanoparticle suspension should change over to the capsule formulation as soon as possible at the discretion of the Investigator.

The dose escalation arms are described as follows:

  • Arms A, B, and C (dose escalation of AZD4635 monotherapy).
  • Arms CA, CB, and CC. In arm CA, the safety, tolerability and PK of the capsule formulation will be assessed in approximately 6 patients with advanced solid malignancies to ensure at least 5 patients have evaluable pharmacokinetic sampling. An additional 12 patients will be enrolled in this arm. Arm CB will assess the safety and tolerability and determine the RP2D of the AZD4635 capsule plus durvalumab and oleclumab in approximately 12 patients. Arm CC will assess the safety, tolerability and determine the RP2D of AZD4635 capsule plus docetaxel in approximately 12 patients .
  • Arms D and E [dose escalation of AZD4635 in combination with durvalumab anti-programmed death-ligand 1 (PD-L1)].

Arms A through E enrolled 38 patients in Phase 1a in order to establish the Recommended Phase 2 Dose (RP2D) of the nanoparticle suspension formulation of AZD4635 as a single agent or in combination with durvalumab.

Arms EA and AA. Arms EA and AA [dose escalation of AZD4635 in combination with either abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castrate-resistant prostate cancer (mRCPC)]. The AZD4635 plus hormonal therapy cohorts will enroll concurrently. Patients who previously received abiraterone acetate, enzalutamide, or apalutamide as part of their prior treatments for mCRPC may be enrolled to the enzalutamide plus AZD4635 arm (Cohort EA) or the abiraterone acetate plus AZD4635 arm (Cohort AA) at the discretion of the Investigator. Approximately 24 to 48 patients with mCRPC will be treated in the AZD4635 plus hormonal therapy arms in order to establish the RP2D.

In Phase 1a approximately 90-132 patients will be treated with AZD4635 as a single agent or in combination with durvalumab, durvalumab plus oleclumab, docetaxel, abiraterone acetate or enzalutamide.

The second segment of the study, designated Phase 1b, will further assess the safety and preliminary activity in the expansion arms described below.

  • Arm F - AZD4635 in combination with durvalumab. Post-immunotherapy non-small cell lung cancer (NSCLC). [15 patients]
  • Arm G - AZD4635 monotherapy. Post-immunotherapy NSCLC. [15 patients]
  • Arm H - AZD4635 monotherapy. Immune checkpoint resistant malignancies, previously treated with approved immunotherapy and progressed or responded and then stopped responding (e.g. renal cell carcinoma, head and neck carcinoma, or MSI high cancers which have approved settings for anti-PD-1 treatment).[20 patients]
  • Arm I - AZD4635 in combination with durvalumab. Immune checkpoint nave mCRPC.[40 patients]
  • Arm J - AZD4635 monotherapy. Immune checkpoint nave CRPC. [40 patients]
  • Arm K - AZD4635 monotherapy. Immune checkpoint nave colorectal carcinoma (CRC). CRC, excluding MSI high, which has not been treated with immune checkpoint inhibitors. [20 patients]
  • Arm KD - AZD4635 in combination with durvalumab. Immune checkpoint nave CRC. CRC, excluding MSI high, which has not been treated with immune checkpoint inhibitors. [20 patients]
  • Arm L - AZD4635 monotherapy. Other solid tumours immune checkpoint nave. Relapsed/refractory tumors which have not been treated with immune checkpoint inhibitors. [20 patients]

Patients will be randomly assigned between open-label arms with AZD4635 monotherapy and AZD4635 combined with durvalumab in NSCLC (Arms F/G) and mCRPC (Arms I/J) in order to minimize bias.

Patients with CRC, excluding MSI high, will be enrolled to AZD4635 monotherapy (Arm K) and AZD4635 combined with durvalumab (Arm KD) in patients with CRC.

Some arms will have a mandatory biopsy subgroup to ensure sufficient tissue is collected to assess the mechanism of action in tissue without excluding patients with nonbiopsiable disease. Biopsies are optional in all other arms.

Clinical Study Identifier: NCT02740985

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Recruitment Status: Open


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