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First Time in Human Study of AZD8701 With or Without Durvalumab in Participants With Advanced Solid Tumours

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04504669
Recruitment Status : Recruiting
First Posted : August 7, 2020
Last Update Posted : September 22, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
The purpose of this study is to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Antitumor Activity of AZD8701 Alone and in Combination with Durvalumab (MEDI4736) in Adult Subjects with Select Advanced Solid Tumors

Condition or disease Intervention/treatment Phase
Clear Cell Renal Cell Cancer Non-Small-Cell Lung Cancer Triple Negative Breast Neoplasms Squamous Cell Cancer of Head and Neck Small Cell Lung Cancer Gastric Cancer Melanoma Cervical Cancer Advanced Solid Tumours Drug: AZD8701 Biological: Durvalumab Phase 1

Detailed Description:

This is a Phase I, First in Human, multicentre, open-label, multiple arm study with dose escalations and expansions at selected doses. Dose-escalation will occur with AZD8701 in monotherapy (Part 1) and in combination with durvalumab (Part 3) in selected participants with HNSCC, TNBC, NSCLC, ccRCC, gastric cancer, melanoma, cervical cancer, small-cell lung cancer and/or participants with solid tumours who have demonstrated a response to prior PD-(L)1 treatment.

Disease specific expansions will occur with a selected dose AZD8701 in participants with NSCLC (Part 2) and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC (Part 4).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

This is a Phase I, FIH, multicentre, open-label, multiple arm study. Dose-escalation will occur with AZD8701 in monotherapy and in combination with durvalumab in selected participants with HNSCC, TNBC, NSCLC, ccRCC, gastric cancer, melanoma, cervical cancer, small-cell lung cancer and/or participants with solid tumours who have demonstrated a response to prior PD-(L)1 treatment.

Disease specific expansions will occur with a selected dose of AZD8701 in participants with NSCLC and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC.

Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: A Phase I First-in-Human Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD8701 Administered Intravenously as Monotherapy and in Combination With Durvaluamb (MEDI4736) in Participants With Advanced Solid Tumours.
Actual Study Start Date : August 25, 2020
Estimated Primary Completion Date : September 7, 2023
Estimated Study Completion Date : September 7, 2023


Arm Intervention/treatment
Experimental: Monotherapy
Participants will receive AZD8701 intravenously, on Day 1, 3, 5 and 8 and then weekly for a maximum of 2 years.
Drug: AZD8701
FOXP3 antisense oligonucleotide

Experimental: Combination Therapy
Participants will receive AZD8701 (intravenously, on Day 1, 3, 5 and 8 and then weekly) and durvalumab (MEDI4736) intravenously monthly for a maximum of 2 years.
Drug: AZD8701
FOXP3 antisense oligonucleotide

Biological: Durvalumab
anti PDL-1 monoclonal antibody
Other Name: MEDI4736




Primary Outcome Measures :
  1. Maximum Tolerated dose (or optimal dose or maximum feasible dose) and RP2D of AZD8701 as monotherapy and in combination with Durvalumab assessed through evaluation of AEs and SAEs [ Time Frame: From screening until 105 days after last dose of study treatment ]
    Determined according to Incidence and treatment related AEs and SAEs

  2. Maximum Tolerated dose (or optimal dose or maximum feasible dose) and RP2D of AZD8701 as monotherapy and in combination with Durvalumab assessed through evaluation of Dose Limiting Toxicities (DLTs) [ Time Frame: First 28 day cycle ]
    Determined according to Incidence of DLTs (during the first 28 day cycle)

  3. Maximum Tolerated dose (or optimal dose or maximum feasible dose) and RP2D of AZD8701 as monotherapy and in combination with Durvalumab assessed through evaluation of vital signs and abnormal laboratory parameters [ Time Frame: From screening until 105 days after last dose of study treatment ]
    Determined according to Incidence of abnormal vital signs and laboratory parameters

  4. Incidence of AEs and SAEs related to AZD8701 as monotherapy and in combination with Durvalumab in disease specific expansions treated at the MTD/OBD/MFD [ Time Frame: From screening until 105 days after last dose of study treatment ]
    Safety and tolerability of the MTD/OBD/MFD assessed through incidence of AEs and SAEs

  5. Objective Response Rate according to RECIST 1.1 by investigator assessment in disease specific expansions treated at the MTD/OB/MFD [ Time Frame: From screening to confirmed disease progression or discontinuation of AZD8701 ]
    The proportion of subjects achieving a confirmed complete or partial response


Secondary Outcome Measures :
  1. Progression-free survival according to RECIST 1.1 by investigator assessment [ Time Frame: every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months) ]
    Time from start of study treatment to the date of objective disease progression or death (by any cause in the absence of progression)

  2. Duration of Response according to RECIST 1.1 by investigator assessment [ Time Frame: every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months) ]
    Time from first documented response (that is subsequently confirmed) to the date of objective disease progression or death (by any cause in the absence of progression)

  3. Disease Control Rate at 16 weeks according to RECIST 1.1 by investigator assessment [ Time Frame: Every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months) ]
    The proportion of subjects with a best response of CR or PR in first 16 weeks or SD for at least 16 weeks

  4. Time to Response according to RECIST 1.1 by investigator assessment [ Time Frame: Every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death or end of study (for max 42 months) ]
    Time from the start of study treatment until the date of first documented response (which is subsequently confirmed)

  5. Best percentage change in tumour size according to RECIST 1.1 by investigator assessment [ Time Frame: Every 8 weeks (first 48 weeks) and then every 12 weeks from start of treatment until the earlier of progression, death, start of subsequent anti-cancer therapy or end of study (for max 42 months) ]
    Best percentage change from baseline in sum of the diameters of target lesions

  6. Overall Survival at 18 months [ Time Frame: From start of treatment to earlier of death or end of study (for max 42 months) ]
    Time from start of treatment until death from any cause.

  7. Plasma AZD8701 and associated PK parameters when administered as monotherapy and in combination with Durvalumab [ Time Frame: From around 2 hours before start of first AZD8701 infusion until 105 days after last dose ]
    Data following the single and multiple-dose parts of the study will be analysed through NCA to determine Cmax

  8. Plasma and urine concentrations of AZD8701 and associated PK parameters when administered as monotherapy and in combination with Durvalumab [ Time Frame: From around 2 hours before start of first AZD8701 infusion until 105 days after last dose ]
    Data following the single and multiple-dose parts of the study will be analysed through NCA to determine tmax

  9. Plasma and urine concentrations of AZD8701 and associated PK parameters when administered as monotherapy and in combination with Durvalumab [ Time Frame: From around 2 hours before start of first AZD8701 infusion until 105 days after last dose ]
    Data following the single and multiple-dose parts of the study will be analysed through NCA to determine AUC

  10. Urine concentrations of AZD8701 to assess renal clearance when administered as monotherapy and in combination with Durvalumab [ Time Frame: From around 2 hours before start of first AZD8701 infusion to day 50 ]
    Urine samples will be collected to assess urine concentrations of AZD8701 at a series of timepoints to derive renal clearance

  11. Serum concentrations of Durvalumab and associated PK parameters when administered in combination with AZD8701 [ Time Frame: From before start of first infusion of Durvalumab until 105 days after last dose ]
    The following and other PK parameters may be reported as data allow: Cmax on Cycle 4 Day 1 (end of infusion concentration) and Cmin on Cycle 4 Day 1 (pre-dose concentration).

  12. Change in FOXP3 mRNA expression [ Time Frame: From day 1 to day 29 ]
    Percentage change in FOXP3 mRNA expression from pre-treatment (baseline) to post treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 101 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

The study is comprised of 2 main parts Monotherapy (AZD8701) and Combined Therapy (AZD8701 and Durvalumab).

Inclusion criteria Dose escalation stages:

  • Histological or cytological confirmation of a solid, malignant tumour including HNSCC, TNBC, NSCLC, ccRCC, gastric cancer, melanoma, cervical cancer, SCLC, and/or participants with other solid tumours who have demonstrated a response to prior anti-PD-(L)1 treatment
  • Participant with progressive disease that is refractory to standard therapies or for which no standard therapies exist and a clinical trial is the best option for next treatment based on prior response and/or tolerability to standard of care

Inclusion Criteria Dose Expansions:

Non Small Lung Cancer Participants who have received prior PD(L)1 treatment. Clear Cell Renal Cancer Participants who have not received prior PD(L)1 treatment.

Triple negative Breast Cancer participants who have who have not received prior PD(L)1 treatment.

General inclusion criteria:

  • Must be 18 year old at the time of screening
  • Body weight > 35 kg
  • Male and Female participants of childbearing potential must use effective methods of contraception
  • Capable of giving signed informed consent
  • ECOG performance status of 0 to 1
  • A serum albumin > 35g/L
  • Life expectancy of > 12 weeks
  • At least 1 lesion, that qualifies as a RECIST 1.1 target lesion at baseline. Tumour assessment by CT scan or MRI must be performed within 28 days prior to treatment.
  • Participants must provide a new or previous tumour sample
  • Adequate organ system functions

Exclusion Criteria:

  • A condition that, in the opinion of the Investigator, would interfere with evaluation of the study intervention or interpretation of participant safety or study results
  • History of allogeneic organ transplantation.
  • Active or prior documented autoimmune or inflammatory disorders Uncontrolled intercurrent illness
  • Significant cardiac disease
  • History of another primary malignancy except for

    1. Malignancy treated with curative intent and with no known active disease ≥ 5 years
    2. non-melanoma skin cancer
    3. Adequately treated carcinoma in situ without evidence of disease.
  • Any major unresolved toxicity from previous anticancer therapy
  • Known allergy or hypersensitivity to any of the study interventions or any of the study intervention excipients.

Prior/Concomitant Therapy

  • Receipt of the last dose of anticancer therapy within 5 half-lives or ≤ 21 days prior to the first dose of study
  • Prior treatment with potential Treg depletion therapies including agents targeting CTLA-4 for 90 days prior to enrolment on study.
  • Participants who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4:

    1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
    2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline
    3. Must not have experienced a ≥ Grade 3 imAE or a neurologic or ocular imAE of any grade while receiving prior immunotherapy.
    4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of study drug. b. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection).
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
  • Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment
  • Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study intervention.
  • Major surgical procedure within 28 days prior to the first dose
  • Participants receiving anticoagulation treatment for venous or arterial indications
  • Participation in another clinical study with study intervention administered in the last 30 days
  • Female participants who are pregnant or breastfeeding or male and female participants of reproductive potential who are not willing to employ effective birth control

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): NCT04504669


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Maryland
Research Site Not yet recruiting
Baltimore, Maryland, United States, 21287
United States, Missouri
Research Site Not yet recruiting
Saint Louis, Missouri, United States, 63110
United States, North Carolina
Research Site Recruiting
Huntersville, North Carolina, United States, 28078
United States, Tennessee
Research Site Not yet recruiting
Franklin, Tennessee, United States, 37067
United States, Texas
Research Site Not yet recruiting
Houston, Texas, United States, 77030
United States, Wisconsin
Research Site Not yet recruiting
Madison, Wisconsin, United States, 53792
Canada, Ontario
Research Site Not yet recruiting
Toronto, Ontario, Canada, M5G 2M9
France
Research Site Not yet recruiting
Villejuif Cedex, France, 94805
Spain
Research Site Not yet recruiting
Barcelona, Spain, 08035
Research Site Not yet recruiting
Pamplona, Spain, 31008
Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04504669    
Other Study ID Numbers: D9950C00001
2019-004539-22 ( EudraCT Number )
First Posted: August 7, 2020    Key Record Dates
Last Update Posted: September 22, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

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 deidentified 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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Solid Tumours
Durvalumab
MEDI4736
AZD8701
Non Small cell Lung cancer
ccRenal Cancer
TNBC
first time in human
PD-L1
T regulatory cells
FOXP3
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Small Cell Lung Carcinoma
Breast Neoplasms
Carcinoma, Renal Cell
Neoplasms, Squamous Cell
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Triple Negative Breast Neoplasms
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplasms by Histologic Type
Urogenital Neoplasms
Breast Diseases
Skin Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Kidney Neoplasms
Urologic Neoplasms
Kidney Diseases
Urologic Diseases
Durvalumab
Antineoplastic Agents, Immunological