A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies
Condition: Advanced Solid Malignancies; Non-Small Cell Lung Cancer (NSCLC); Metastatic Castrate-Resistant Prostate Carcinoma (mCRPC); Colorectal Carcinoma (CRC)
MeSH terms: Carcinoma; Carcinoma, Non-Small-Cell Lung; Neoplasms; Colorectal Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      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 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 naïve mCRPC.[40
           patients]

        -  Arm J - AZD4635 monotherapy. Immune checkpoint naïve CRPC. [40 patients]

        -  Arm K - AZD4635 monotherapy. Immune checkpoint naïve 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 naïve 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 naïve.
           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.
    

Intervention name(s): AZD4635; Durvalumab; Abiraterone Acetate; Enzalutamide; Oleclumab; Docetaxel
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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 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 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 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 1500 mg will be given by IV infusion on Days 1 and 15 of each cycle.; 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.
Other intervention name(s): MEDI4736; Zytiga; Xtandi; MEDI9447; Taxotere
Intervention MeSH terms: Docetaxel; Durvalumab; Abiraterone Acetate
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AZD4635; durvalumab; oleclumab; docetaxel; non-small cell lung cancer; advanced solid malignancies; prostate cancer; colorectal cancer; abiraterone acetate; enzalutamide