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

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.

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

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma; Cervical Cancer; Small Cell Lung Cancer; Triple Negative Breast Neoplasms; Advanced Solid Tumours; Non-Small-Cell Lung Cancer; Gastroesophageal Cancer; Clear Cell Renal Cell Cancer; Squamous Cell Cancer of Head and Neck
• Intervention / Treatment: Drug: AZD8701; Biological: Durvalumab

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, gastroesophageal 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 (Part 2) and with a selected dose of AZD8701 and durvalumab in participants with TNBC and clear cell RCC (Part 4).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
• France
  • Rennes, France, 35000
    • Research Site
  • Villejuif Cedex, France, 94805
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • L'Hospitalet de Llobregat, Spain, 08907
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28027
    • Research Site
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Research Site
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 101 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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, gastroesophageal 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 > 30g/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.
• Participant with previous or confirmed Covid 19 diagnosis requiring significant medical intervention
• Current clinical signs and symptoms consistent with COVID-19 or confirmed current infection by appropriate laboratory test within the last 4 weeks prior to screening
• 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 OX40 or CD357 (GITR) 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 therapy with vitamin K antagonists (eg warfarin)
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: MEDI4736

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Determined according to Incidence and treatment related AEs and SAEs	From screening until 105 days after last dose of study treatment
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)	Determined according to Incidence of DLTs (during the first 28 day cycle)	First 28 day cycle
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	Determined according to Incidence of abnormal vital signs and laboratory parameters	From screening until 105 days after last dose of study treatment
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	Safety and tolerability of the MTD/OBD/MFD assessed through incidence of AEs and SAEs	From screening until 105 days after last dose of study treatment
Objective Response Rate according to RECIST 1.1 by investigator assessment in disease specific expansions treated at the MTD/OB/MFD	The proportion of subjects achieving a confirmed complete or partial response according to RECIST 1.1 by investigator assessment	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival according to RECIST 1.1 by investigator assessment	Time from start of study treatment to the date of objective disease progression or death (by any cause in the absence of progression)	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)
Duration of Response according to RECIST 1.1 by investigator assessment	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)	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)
Disease Control Rate at 16 weeks according to RECIST 1.1 by investigator assessment	The proportion of subjects with a best response of CR or PR in the first 16 weeks or SD for at least 16 weeks according to RECIST 1.1 by investigator assessment	Every 8 weeks from start of treatment until earlier of progression, death or start of subsequent anti-cancer therapy (for up to 24 weeks). Subjects followed to 24 weeks for assessment of SD for 16 weeks from first tumour assessment at 8 weeks
Time to Response according to RECIST 1.1 by investigator assessment	Time from the start of study treatment until the date of first documented response (which is subsequently confirmed)	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)
Best percentage change in tumour size according to RECIST 1.1 by investigator assessment	Best percentage change from baseline in sum of the diameters of target lesions	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)
Overall Survival at 18 months	The survival rate of subjects at 18 months from start of treatment	From start of treatment until the earlier of death or end of study (for max of 42 months). Each subject is followed for a minimum of 18 months and the landmark OS rate at 18 months will be estimated using a Kaplan-Meier analysis
Maximum concentration (Cmax) of AZD8701 in plasma when administered as monotherapy and in combination with Durvalumab	Maximum concentration (Cmax) of AZD8701 in plasma	Cycle 1: Day 1, 2, 3, 5, 8. Cycle 2: Day 1, 22, 23. Cycle 3 & 4: Day 1 and at 105 day follow up (up to 28 months)
Time to maximum concentration (tmax) of AZD8701 in plasma when administered as monotherapy and in combination with Durvalumab	Time to maximum concentration (tmax) of AZD8701 in plasma	Cycle 1: Day 1, 2, 3, 5, 8. Cycle 2: Day 1, 22, 23. Cycle 3 & 4: Day 1 and at 105 day follow up (up to 28 months)
Exposure to AZD8701 through measurement of area under the curve (AUC) in plasma when administered as monotherapy and in combination with Durvalumab	Exposure to AZD8701 through measurement of area under the curve (AUC) in plasma	Cycle 1: Day 1, 2, 3, 5, 8. Cycle 2: Day 1, 22, 23. Cycle 3 & 4: Day 1 and at 105 day follow up (up to 28 months)
Maximum concentration (Cmax) of AZD8701 in urine when administered as monotherapy and in combination with Durvalumab	Maximum concentration (Cmax) of AZD8701 in urine	Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Time to maximum concentration (tmax) of AZD8701 in urine when administered as monotherapy and in combination with Durvalumab	Time to maximum concentration (tmax) of AZD8701 in urine	Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Exposure to AZD8701 through measurement of area under the curve (AUC) in urine when administered as monotherapy and in combination with Durvalumab	Exposure to AZD8701 through measurement of area under the curve (AUC) in urine	Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Urine concentrations of AZD8701 to assess renal clearance when administered as monotherapy and in combination with Durvalumab	Urine samples will be collected to assess urine concentrations of AZD8701 at a series of timepoints to derive renal clearance	Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)
Maximum concentration (Cmax) of Durvalumab in serum when administered in combination with AZD8701	Maximum concentration (Cmax) of Durvalumab in serum	Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months)
Minimum concentration (Cmin) of Durvalumab in serum when administered in combination with AZD8701	Minimum concentration (Cmin) of Durvalumab in serum	Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months)
Change in FOXP3 mRNA expression	Percentage change in FOXP3 mRNA expression from pre-treatment (baseline) to post treatment	From day 1 to day 29

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Revenko A, Carnevalli LS, Sinclair C, Johnson B, Peter A, Taylor M, Hettrick L, Chapman M, Klein S, Solanki A, Gattis D, Watt A, Hughes AM, Magiera L, Kar G, Ireland L, Mele DA, Sah V, Singh M, Walton J, Mairesse M, King M, Edbrooke M, Lyne P, Barry ST, Fawell S, Goldberg FW, MacLeod AR. Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer. J Immunother Cancer. 2022 Apr;10(4):e003892. doi: 10.1136/jitc-2021-003892.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2020
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): January 31, 2025

Study Registration Dates

• First Submitted: July 16, 2020
• First Submitted That Met QC Criteria: August 5, 2020
• First Posted (Actual): August 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: first time in human; PD-L1; T regulatory cells; TNBC; Durvalumab; Solid Tumours; MEDI4736; AZD8701; Non Small cell Lung cancer; ccRenal Cancer; FOXP3
• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Breast Neoplasms; Head and Neck Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Carcinoma, Squamous Cell; Triple Negative Breast Neoplasms; Neoplasms, Squamous Cell; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab
• Other Study ID Numbers: D9950C00001; 2019-004539-22 (EudraCT Number); 04504669 (Other Identifier: NCT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No