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

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ClinicalTrials.gov Identifier: NCT02740985
Recruitment Status : Recruiting
First Posted : April 18, 2016
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This is a Phase I, open-label, multicenter study of continuous oral dosing of AZD4635 administered as a single agent and then in combination with a PD-L1 antibody, durvalumab. The study design allows an escalation of dose with intensive safety monitoring to ensure the safety of the patients. The primary objective of the study is to determine the maximum tolerated dose of AZD4635 in combination with durvalumab.

Condition or disease Intervention/treatment Phase
Advanced Solid Malignancies Non-Small Cell Lung Cancer (NSCLC) Metastatic Castrate-Resistant Prostate Carcinoma (mCRPC) Colorectal Carcinoma (CRC) Drug: AZD4635 Drug: Durvalumab Phase 1

Detailed Description:

The study will be conducted in two segments. The first segment of the study (Phase 1a) will be a dose escalation design in order to determine the Maximum Tolerated Dose (MTD) of AZD4635 given as monotherapy and in combination with durvalumab. The MTD will be determined by assessing adverse events and the incidence of abnormal laboratory measures. Once the maximum tolerated monotherapy dose of AZD4635 has been determined, combination dosing with durvalumab will start in a new cohort of patients at one dose level lower than the highest tolerated dose of AZD4635 monotherapy. The combination therapy cohorts in Phase 1a will also have a 2-week monotherapy lead-in after which patients who tolerate monotherapy AZD4635 will then continue twice daily dosing of AZD4635 in combination with durvalumab (anti programmed-death ligand 1 [PD-L1]) at the fixed dose of 1.5 grams IV every 4 weeks.

When the maximum-tolerated dose in the combination setting is determined, additional patients with advanced solid malignancies will be enrolled to a dose expansion portion to explore further the safety, tolerability, pharmacokinetics (PK), and biological activity at the selected doses. Approximately 24 to 42 patients with advanced solid malignancies will be treated in Phase 1a. When the maximum-tolerated dose in the combination setting is determined, additional patients with advanced solid malignancies will be enrolled to a dose expansion portion to explore further the safety, tolerability, pharmacokinetics (PK), and biological activity at the selected doses. Approximately 24 to 42 patients with advanced solid malignancies will be treated in Phase 1a. If the MTD for either AZD4635 monotherapy or the AZD4635/durvalumab combination is not reached dose expansion may take place at dose levels of AZD4635 and durvalumab other than MTD.

The second segment of the study (Phase 1b) will consist of an additional expansion cohorts in tumour types where there is a rationale for potential efficacy of the study treatment. The additional dose expansion cohorts will use doses that do not exceed the highest tolerated dose determined during the dose escalation segment of the study in patients with:

  • Post-immunotherapy non-small cell lung cancer (NSCLC) (AZD4635 monotherapy or AZD4635 in combination with durvalumab).
  • Other post-immunotherapy solid tumours (AZD 4635 monotherapy).
  • Immune checkpoint-naïve metastatic castrate-resistant prostate carcinoma (mCRPC) (AZD4635 monotherapy or AZD4635 in combination with durvalumab).
  • Immune checkpoint-naïve colorectal carcinoma (CRC) (AZD4635 monotherapy).
  • Other immune checkpoint-naïve solid tumours (AZD4635 monotherapy).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 208 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-Label, Multicenter Study to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Tumor Activity of Ascending Doses of AZD4635 Both as Monotherapy and in Combination With Durvalumab in Patients With Advanced Solid Malignancies
Actual Study Start Date : June 17, 2016
Estimated Primary Completion Date : May 13, 2020
Estimated Study Completion Date : May 13, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: AZD4635 Monotherapy

AZD4635 monotherapy will be given twice daily in a dose escalation scheme in Part 1a. Patients will receive a single dose of AZD4635 on Day 1 and will have blood samples collected to assess pharmacokinetics over 24 hours. On Day 2, twice daily dosing will commence and continue daily. Other dosing schedules (e.g., once daily, three times daily) may be investigated during the study on the basis of emerging safety, PK, and exploratory mechanism of action (MOA) data. During monotherapy dosing, a cycle will be 3 weeks. The Safety Review Committee (SRC) will determine whether dose escalation should occur based on safety assessments in the first cycle supported by a Bayesian Logistic Regression Model (BLRM) approach.

In Phase 1b additional expansion cohorts will be investigated based on the activity observed in the Phase 1a monotherapy dose escalation cohorts as well as monotherapy responses seen in other A2aR inhibitor studies.

Drug: AZD4635
AZD4635 will be administered orally as a nanosuspension on a continuous schedule. The drug product will be constituted extemporaneously as an oral suspension by the patient immediately prior to dosing.

Experimental: AZD4635 + Durvalumab Combination

In the combination therapy cohorts AZD4635 will be given as monotherapy during a 2-week lead-in. After the 2-week lead-in durvalumab will be given by IV infusion on Day 1 of each 4-week cycle. Other dosing schedules (e.g., once daily, three times daily) may be investigated during the study on the basis of emerging safety, PK, and exploratory mechanism of action (MOA) data. During combination therapy dosing, a cycle will be 4 weeks. The Safety Review Committee (SRC) will determine whether dose escalation should occur based on safety assessments in the first cycle supported by a Bayesian Logistic Regression Model (BLRM) approach.

In Phase 1b additional expansion cohorts receiving combination therapy with AZD4635 and durvalumab will be investigated in patients with non small-cell lung cancer or metastatic castrate-resistant prostate cancer.

Drug: AZD4635
AZD4635 will be administered orally as a nanosuspension on a continuous schedule. The drug product will be constituted extemporaneously as an oral suspension by the patient immediately prior to dosing.

Drug: Durvalumab
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.
Other Name: MEDI4736




Primary Outcome Measures :
  1. The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 monotherapy orally. [ Time Frame: 3 weeks (One Cycle) ]
    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%. It is planned that 24 to 36 patients in total will be included in the dose-escalation part of Phase Ia. In each cohort, up to 3 patients will be initially assessed. Dose escalation to the next higher dose level for the next cohort group of 3 patients will occur if all 3 patients in the initial cohort complete the first 3 weeks of dosing 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.

  2. The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 orally in combination with intravenous durvalumab. [ Time Frame: 4 weeks (One Cycle) ]
    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%. It is planned that 24 to 36 patients in total will be included in the dose-escalation part of Phase Ia. In each cohort, up to 3 patients will be initially assessed. Dose escalation to the next higher dose level for the next cohort group of 3 patients will occur if all 3 patients in the initial cohort complete the first 3 weeks of dosing 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.


Secondary Outcome Measures :
  1. The plasma concentration of AZD4635 after administration in the monotherapy portion of the study [ Time Frame: PK sampling will be done on 1 of 3 schedules: Intensive AZD4635 PK, ECG-matched AZD4635 PK, or Sparse AZD4635 PK. Samples will be collected at pre-specified time points over 24 hr on Day 1 of Cycle 1 and predose on Day 1 of additional Cycles. ]
    The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.

  2. The concentration of AZD4635 and metabolites in urine [ Time Frame: A predose sample of urine will be collected. Quantitative collection of all urine will done in the following post-dose intervals: 0-4 hours, 4-8 hours, and 8-24 hours. ]
    The amount of AZD4635 (and metabolites) in urine will be determined in all patients. Pooled collections of urine 0 to 4 hours post dose, 4 to 8 hours post dose, and 8 to 24 hours post dose. Patients will collect all urine at home and bring the 8 to 24 hour pooled collection to the clinic. The total volume of each pooled sample will be recorded after which a 10 mL aliquot will be taken for analysis.

  3. The plasma concentration of AZD4635 when given in combination with durvalumab [ Time Frame: Sampling will be done on 1 of 3 schedules: Intensive AZD4635 PK, ECG-matched AZD4635 PK, or Sparse AZD4635 PK. Samples will be taken at various time points over 24 hr on Day 1, Cycles 1, 2, & 4, predose Day 15, Cycle 2, and predose on Day 1 of odd Cycles ]
    Plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. The date and time of collection of each sample will be recorded.

  4. The concentration of durvalumab and anti-drug antibody in plasma when given in combination with AZD4635 [ Time Frame: Preinfusion and end of infusion on Day 1 of Cycles 2 and 5. Preinfusion of Day 1 of Cycles 3 and 8 and 90-days after the last dose of durvalumab. ]
    Plasma concentration of durvalumab and anti-drug antibody will be determined by inspection of the concentration-time profile. The date and time of collection of each sample will be recorded.

  5. The effect of AZD4635 on QTc interval [ Time Frame: In screening and on Days 1, 2 and 15 in Cycle 1, Day 1 of each cycle thereafter, and at the end of treatment and at each progression-free follow-up visit. ]
    Twelve-lead ECGs will be obtained after the patient has been resting supine for at least 10 minutes. For each time point 3 ECG recordings should be taken at about 2- to 5 minute intervals.

  6. Tumour Response [ Time Frame: Tumour response will be assessed 6 weeks after the start of treatment and then every 8 weeks thereafter up to 1 year. ]

    Categorization of objective tumour response assessment will be based on the RECIST Version 1.1 guidelines for response (CR (complete response), PR (partial response), SD (stable disease), and PD (progressive disease).

    For patients who only have non-measurable disease at baseline, categorization of objective tumour response assessment will be based on the RECIST Version 1.1 guideline for response for non-target lesions (NTLs): CR, PD, and Non CR/Non PD.




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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. 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.
  2. Age ≥ 18.
  3. Availability of an archival tumor tissue sample. If archival tumour tissue is not available, then tissue from a fresh biopsy can be used.
  4. Patients in the Phase 1a dose escalation combination cohorts must have at least 1 tumour lesion amenable to biopsy and must be medically fit and willing to undergo a biopsy during screening and, unless clinically contraindicated, after 2 weeks on monotherapy.
  5. Phase 1a: histological or cytological confirmation of a solid, malignant tumor, excluding CNS tumors, that is refractory to standard therapies or for which no standard therapies exist.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 with no clinical deterioration over the previous 2 weeks and likely able to complete at least 9 weeks of treatment.
  7. Normotensive or well controlled blood pressure (<140/90).
  8. 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.
  9. Male patients should be willing to use barrier contraception for the duration of the study and for 3 months after treatment discontinuation.

Inclusion Criteria for Phase 1b Expansion Cohorts

  1. Patients must have disease that is suitable for repeated measurement, either

    - At least one lesion that can be accurately assessed at baseline by computed tomography (TC), magnetic resonance imaging (MRI) or X-ray, that is suitable for repeated measurement,

    OR

    - Patients with mCRC must have measurable PSA above normal limits per local ranges.

  2. A minimum of 10 patients with mCRPC, CRC and 'other' tumors will be required to have a site of disease that is safely accessible for biopsy (paired) upon enrollment. Accessible lesions are defined as those which are biopsiable (at screening) and amenable to repeat biopsy (after 2 weeks of monotherapy), unless clinically contraindicated. In the case that the second sample is not taken, the patient will remain in the study and there will be no penalty or loss of benefit to the patient and they will not be excluded from other aspects of the study.

    The tumor-specific cohorts will be closely monitored to ensure the desired number of biopsiable patients are enrolled. The requirement for biopsies must be made clear to each patient at the time of initial approach by the Investigator.

  3. For post immunotherapy patients with NSCLC all of the following apply:

    • Patients must have advanced or metastatic NSCLC with histological or cytological confirmation. Patients with known EGFR-activating mutations or ALK rearrangements are excluded.
    • Patient must have previously received one (but no more) line of previous therapy with an anti-PD-1/PD-L1 mAb therapy either alone or in combination and have either progressed or responded and then stopped responding.
  4. For other post immunotherapy patients all of the following must apply:

    • Patients must have an immune checkpoint resistant malignancy (for example, RCC, head and neck carcinoma or MSI high cancers which have approved settings for anti-PD1 treatment), confirmed histologically or cytologically.
    • Patients must have previously received at least one line (and not more than 2 lines) of previous therapy with an anti-PD-1/PD-L1 mAb therapy, either alone or in combination, and have either progressed or responded and then stopped responding.
  5. For immune checkpoint naïve CRPC patients all of the following must apply:

    • Patients must have metastatic prostate cancer with histological or cytological confirmation.
    • 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 with gonadotropin-releasing hormone analogues should continue this treatment during this study.
    • Patients must have previously received and progressed on standard-of-care therapy(ies).
    • Approximately 60 out of 80 patients with mCRPC enrolled must have measurable disease (approximately 30 out of 40 in each of the mCRPC Cohorts) that is suitable for repeated measurements. Enrollment will be monitored to ensure the required number of patients with measurable disease enter the study.
  6. For immune checkpoint naïve patients all of the following must apply:

    • Must have immune checkpoint naïve histologically/cytologically confirmed advanced or metastatic CRC.
    • Must have previously received and progressed on at least 1 prior chemotherapy regimen.
  7. For other immune checkpoint naïve tumor cohort all of the following must apply:

    • Patients with other immune checkpoint naïve histologically/ cytologically confirmed advanced solid tumor type that has received and progressed on standard-of-care therapy(ies).

Exclusion Criteria

  1. Treatment with any of the following:

    • Nitrosourea or mitomycin C within 6 weeks of the first dose
    • Any investigational agents or drugs from a previous clinical study within 28 days
    • Any small molecule, biologic, or hormonal agent within 21 days or a washout period equal to 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.
    • Any investigational medicinal product or other systemic chemotherapy, or antibody therapy within 4 weeks prior to the first dose of study treatment, or within 8 weeks after immunotherapy, whichever is the most appropriate and as judged by the Investigator. Note: androgen-deprivation therapy is permitted for patients with prostate cancer.
    • 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 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks 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.
    • Concomitant medications with another A1R antagonist that would increase the risk of seizure (e.g., theophylline, aminophylline).
    • Ongoing treatment with Coumadin.
    • AZD4635 in a different cohort in this study.
    • Ongoing corticosteroid use.
    • Major surgery within 4 weeks of the first dose of study treatment
    • Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment.
  2. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
  3. History of seizures, central nervous system tumors or CNS metastasis. Due to the incidence of silent CNS metastases in patients with advanced NSCLC, such patients must undergo mandatory screening with brain MRI or CT scan to determine eligibility.
  4. Significant mental illness in the 4-week period preceding drug administration.
  5. Evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension, active bleeding diatheses, or active infection.
  6. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 ECGs
    • Clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
    • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
    • Any factors that increase the risk of QTc prolongation or risk of rrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
    • Ejection fraction < 55% or less than the lower limit of normal of the institutional standard.
  7. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    • Absolute neutrophil count < 1.5 x 10 (exp9)/L
    • Platelet count < 100 x 10 (exp9)/L
    • Hemoglobin <90 g/L
    • ALT and/or AST >2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
    • Total bilirubin >1.5 times ULN
    • Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min
  8. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant bowel resection that would preclude adequate absorption of AZD4635.
  9. Any patient with an open oral ulceration(s) should avoid dosing with AZD4635 oral suspension.
  10. Organ transplant that requires the use of immunosuppressive treatment.
  11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis, celiac disease, systemic lupus erythematous, Wegner's syndrome, myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune nephritis or nephropathy, etc.) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

    • Vitiligo or alopecia.
    • Hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
    • Psoriasis or eczema not requiring systemic treatment.
  12. Patients with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions following prior anti-PD-1 or other immune-oncology therapies
  13. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or class to AZD4635.
  14. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and/or requirements.
  15. Enrollment into another therapeutic clinical trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02740985


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AstraZeneca Cancer Study Location Service 1-877-400-4656 AstraZeneca@emergingmed.com

Locations
United States, California
Research Site Recruiting
Fresno, California, United States, 93720
United States, Colorado
Research Site Recruiting
Denver, Colorado, United States, 80218
United States, Connecticut
Research Site Not yet recruiting
New Haven, Connecticut, United States, 06519
United States, Florida
Research Site Not yet recruiting
Daytona Beach, Florida, United States, 32117
Research Site Not yet recruiting
Lecanto, Florida, United States, 34461
Research Site Not yet recruiting
North Port, Florida, United States, 34288
Research Site Recruiting
Sarasota, Florida, United States, 34232
United States, Illinois
Research Site Recruiting
Decatur, Illinois, United States, 62526
United States, Massachusetts
Research Site Not yet recruiting
Boston, Massachusetts, United States, 02215
United States, Nebraska
Research Site Not yet recruiting
Omaha, Nebraska, United States, 68130
United States, Nevada
Research Site Recruiting
Las Vegas, Nevada, United States, 89119
United States, New York
Research Site Recruiting
New York, New York, United States, 10032
United States, North Carolina
Research Site Recruiting
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Research Site Recruiting
Philadelphia, Pennsylvania, United States, 19107
United States, South Carolina
Research Site Not yet recruiting
Myrtle Beach, South Carolina, United States, 29572
United States, Tennessee
Research Site Not yet recruiting
Chattanooga, Tennessee, United States, 37404
Research Site Recruiting
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
AstraZeneca
Investigators
Study Chair: Johanna Bendell, MD SCRI Development Innovations, LLC

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02740985     History of Changes
Other Study ID Numbers: D8730C00001
REFMAL 435 ( Other Identifier: Sarah Cannon Development Innovations, LLC )
First Posted: April 18, 2016    Key Record Dates
Last Update Posted: October 25, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
AZD4635
durvalumab
non-small cell lung cancer
advanced solid malignancies
prostate cancer
colorectal cancer

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Non-Small-Cell Lung
Neoplasms
Colorectal Neoplasms
Prostatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
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
Prostatic Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs