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

NCT02740985 | Completed Phase 1 FDA Drug

• 2 other identifiers: D8730C00001REFMAL 435
• Study Type: interventional
• Target: 313
• Locations: 1 country
• Sites: 17

Brief 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.

Conditions

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

Keywords

AZD4635; durvalumab; oleclumab; docetaxel; non-small cell lung cancer; advanced solid malignancies; prostate cancer; colorectal cancer; abiraterone acetate; enzalutamide

Outcome Measures

Primary Outcomes (4)

• The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 monotherapy orally.

  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.

  3 weeks (One Cycle)

• The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 in combination with durvalumab.

  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.

  7 weeks (Including Cycle 0)

• The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 in combination with either abiraterone acetate or enzalutamide.

  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.

  21 days (Cycle 1)

• The incidence of adverse events

  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.

  Patients will be followed for either 21 days in Cycles 1 and 2 or 28 days in Cycles 3 and beyond to determine the incidence of adverse events.

Secondary Outcomes (22)

• Peak plasma concentration (Cmax) of AZD4635 after single-dose administration in Cycle 0

  Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.

• Time to peak plasma concentration (tmax) of AZD4635 after single-dose administration in Cycle 0

  Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.

• Terminal elimination rate constant (λz) of AZD4635 after single-dose administration in Cycle 0

  Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.

• Terminal elimination half-life (t½λz) of AZD4635 after single-dose administration in Cycle 0

  Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.

• Area under the plasma concentration-time curve following single dose administration of AZD4635 in Cycle 0

  Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1

Study Arms (18)

Arm A

EXPERIMENTAL

AZD4635 monotherapy as nanoparticle suspension 125 mg BID

Drug: AZD4635

Arm B

EXPERIMENTAL

AZD4635 monotherapy as nanoparticle suspension 75 mg QD

Drug: AZD4635

Arm C

EXPERIMENTAL

AZD4635 monotherapy as nanoparticle suspension 100 mg QD

Drug: AZD4635

Arm D

EXPERIMENTAL

AZD4635 as nanoparticle suspension 75 mg QD plus durvalumab

Drug: AZD4635; Drug: Durvalumab

Arm E

EXPERIMENTAL

AZD4635 as nanoparticle suspension 100 mg QD plus durvalumab

Drug: AZD4635; Drug: Durvalumab

Arm EA

EXPERIMENTAL

AZD4635 as nanoparticle suspension plus enzalutamide

Drug: AZD4635; Drug: Enzalutamide

Arm AA

EXPERIMENTAL

AZD4635 as nanoparticle suspension plus abiraterone acetate

Drug: AZD4635; Drug: 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.

Drug: AZD4635; Drug: Durvalumab

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.

Drug: AZD4635

Arm H

EXPERIMENTAL

AZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with other solid tumours.

Drug: AZD4635

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.

Drug: AZD4635; Drug: Durvalumab

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.

Drug: AZD4635

Arm K

EXPERIMENTAL

AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with colorectal carcinoma.

Drug: AZD4635

Arm KD

EXPERIMENTAL

AZD4635 as nanoparticle suspension plus durvalumab in immunotherapy-naïve patients with colorectal carcinoma.

Drug: AZD4635; Drug: Durvalumab

Arm L

EXPERIMENTAL

AZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with other solid tumours.

Drug: AZD4635

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).

Drug: AZD4635

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.

Drug: AZD4635; Drug: Durvalumab; Drug: Oleclumab

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).

Drug: AZD4635; Drug: Docetaxel

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.

Arm A; Arm AA; Arm B; Arm C; Arm CA; Arm CB; Arm CC; Arm D; Arm E; Arm EA; Arm F; Arm G; Arm H; Arm I; Arm J; Arm K; Arm KD; Arm L

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.

Also known as: MEDI4736

Arm CB; Arm D; Arm E; Arm F; Arm I; Arm KD

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.

Also known as: Zytiga

Arm AA

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.

Also known as: Xtandi

Arm EA

Oleclumab DRUG

Oleclumab 1500 mg will be given by IV infusion on Days 1 and 15 of each cycle.

Also known as: MEDI9447

Arm CB

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.

Also known as: Taxotere

Arm CC

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must consent to the study and provide a signed and dated written informed consent document prior to any study-specific procedures, sampling, or analyses.
• Age ≥18 years
• Weight ≥77 lbs (35 kg)
• Availability of an archival tumor tissue sample. If archival tumor tissue is not available, then tissue from a fresh biopsy can be used.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 w/ no clinical deterioration over the prior 2 weeks (wks) and likely able to complete at least 9 wks of treatment.
• Normotensive or well controlled blood pressure (systolic \<150 and diastolic \<90) w/ or without current anti-hypertensive treatment. If there is a diagnosis or history of hypertension, patient must have adequately controlled BP on antihypertensive medications as demonstrated by 2 BP measurements taken in the clinical setting by a medical professional within 1 week (wk) prior to enrollment. Patients on anti-hypertensive medication must be willing and able to check and record twice daily BP readings for a minimum of 3 wks.
• Females should be using adequate contraceptive measures from the time of screening until 3 months after study discontinuation, should not be breast feeding and must have negative pregnancy test prior to the start of dosing, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
• Post-menopausal: defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.
• Women under 50 years-of-age will be considered postmenopausal if they have been amenorrheic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone and luteinizing hormone levels in the postmenopausal range for the institution.
• Male patients should be willing to use barrier contraception for the duration of the study and for 3 months after treatment discontinuation.
• Ability to swallow and retain oral medication.
• \. Patients in Arms AA and EA must have metastatic prostate cancer w/ histological or cytological confirmation. Note: Patient may have bone only metastatic disease.
• Patients must be castrate-resistant (i.e. developed progression of metastases following surgical castration or during medical androgen ablation therapy). (Patients receiving medical castration therapy w/ gonadotropin-releasing hormone analogues should continue this treatment during this study.)
• Patients must have received prior treatment w/ at least one of the hormonal agents (abiraterone acetate, enzalutamide or apalutamide). Patients who received prior apalutamide will be allocated to abiraterone acetate (Arm AA). Note: Prior chemotherapy is allowed but not required.

You may not qualify if:

• Treatment with any of the following:
• Nitrosourea or mitomycin C within 6 wks of the first dose.
• Any systemic anti-cancer chemotherapy, small molecule, biologic, or hormonal agent from a previous treatment regimen or clinical study within 21 days or 5 half-lives (whichever is shorter). At least 7 days must have elapsed between the last dose of such agent and the first dose of study drug. EXCEPTION: Androgen-deprivation therapy is recommended for patients w/ prostate cancer.
• Enrollment into another therapeutic clinical trial. EXCEPTION: Patients are allowed to participate in investigational imaging or non-therapeutic studies.
• Patient has had Rx or non-Rx drugs or other products known to be sensitive BCRP or OAT1 substrates or to be potent inhibitors/inducers of CYP1A2, which cannot be discontinued 2 wks prior to Day 1 of dosing and withheld throughout the study until 2 wks after the last dose of AZD4635.
• Herbal preparations/medications are not allowed throughout the study, including but not limited to St. John's Wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 7 days prior to the first dose of AZD4635.
• Patient may not be assigned to abiraterone acetate arm (Arm AA) if co-administration of a strong CYP3A4 or a CYP2D6 substrate with a narrow therapeutic index is required during study treatment.
• Patient may not be assigned to an enzalutamide arm (Arm EA) if co-administration of strong CYP2C8 inhibitor, strong or moderate CYP3A4 or CYP2C8 inducer, or CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index is required during study treatment.
• Ongoing treatment w/ Coumadin.
• Concomitant medications w/ another A1R antagonist that would increase risk of seizure (e.g., theophylline or aminophylline).
• AZD4635 in the present study (i.e., dosing w/ AZD4635 previously initiated in a different arm in this study), or prior therapy w/ AZD4635 or any other A2AR antagonist.
• Ongoing corticosteroid use. NOTE: mCRPC patients assigned to an arm with abiraterone acetate (Arm AA) should take prednisone as prescribed for glucocorticoid replacement therapy and patients assigned to the docetaxel arm (Arm CC) should take prophylactic dexamethasone (or equivalent) to prevent severe hypersensitivity reactions.
• Major surgery (excluding placement of vascular access) within 4 wks of the first dose of study treatment.
• Radiotherapy w/ a wide field of radiation within 4 wks or radiotherapy w/ a limited field of radiation for palliation within 2 wks of the first dose of study treatment.
• Patient w/ prior history of myocardial infarction, transient ischemic attack, or stroke within 3 months prior to the scheduled first dose of oleclumab treatment (Arm CB).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (17)

Research Site

Fayetteville, Arkansas, 72703, United States

Location

Research Site

Fresno, California, 93720, United States

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Research Site

Denver, Colorado, 80218, United States

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Research Site

New Haven, Connecticut, 06519, United States

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Daytona Beach, Florida, 32117, United States

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Research Site

Lecanto, Florida, 34461, United States

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Research Site

North Port, Florida, 34288, United States

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Research Site

Sarasota, Florida, 34232, United States

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Research Site

Decatur, Illinois, 62526, United States

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Research Site

Las Vegas, Nevada, 89119, United States

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Research Site

New York, New York, 10032, United States

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Research Site

Durham, North Carolina, 27710, United States

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Research Site

Oklahoma City, Oklahoma, 73104, United States

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Research Site

Philadelphia, Pennsylvania, 19107, United States

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Myrtle Beach, South Carolina, 29572, United States

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Research Site

Chattanooga, Tennessee, 37404, United States

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Research Site

Nashville, Tennessee, 37203, United States

Location

Related Links

• Redacted CSR synopsis

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Prostatic Neoplasms

Interventions

durvalumab; Abiraterone Acetate; enzalutamide; Docetaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Johanna Bendell, MD

  SCRI Development Innovations, LLC

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 29, 2016
• First Posted: April 18, 2016
• Study Start: June 17, 2016
• Primary Completion: December 31, 2020
• Study Completion: March 31, 2023
• Last Updated: May 26, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (17)