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

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04504669

Collaborator

(none)

153

Enrollment

Locations

Arms

41.1

Anticipated Duration (Months)

6.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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 Gastroesophageal 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, 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 Design

Study Type:

Interventional

Anticipated Enrollment :

153 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, gastroesophgeal 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.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, gastroesophgeal 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 :

Aug 18, 2020

Anticipated Primary Completion Date :

Jan 22, 2024

Anticipated Study Completion Date :

Jan 22, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Progression-free survival 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 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)
Duration of 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 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)
Disease Control Rate at 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]
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
Time to 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 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)
Best percentage change in tumour size 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)]
Best percentage change from baseline in sum of the diameters of target lesions
Overall Survival at 18 months [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]
The survival rate of subjects at 18 months from start of treatment
Maximum concentration (Cmax) of AZD8701 in plasma when administered as monotherapy and in combination with Durvalumab [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 plasma
Time to maximum concentration (tmax) of AZD8701 in plasma when administered as monotherapy and in combination with Durvalumab [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
Exposure to AZD8701 through measurement of area under the curve (AUC) in plasma when administered as monotherapy and in combination with Durvalumab [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
Maximum concentration (Cmax) of AZD8701 in urine when administered as monotherapy and in combination with Durvalumab [Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)]
Maximum concentration (Cmax) of AZD8701 in urine
Time to maximum concentration (tmax) of AZD8701 in urine when administered as monotherapy and in combination with Durvalumab [Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)]
Time to maximum concentration (tmax) of AZD8701 in urine
Exposure to AZD8701 through measurement of area under the curve (AUC) in urine when administered as monotherapy and in combination with Durvalumab [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
Urine concentrations of AZD8701 to assess renal clearance when administered as monotherapy and in combination with Durvalumab [Cycle 1: Day 1, 2. Cycle 2: Day 22, 23 (up to 2 months)]
Urine samples will be collected to assess urine concentrations of AZD8701 at a series of timepoints to derive renal clearance
Maximum concentration (Cmax) of Durvalumab in serum when administered in combination with AZD8701 [Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months)]
Maximum concentration (Cmax) of Durvalumab in serum
Minimum concentration (Cmin) of Durvalumab in serum when administered in combination with AZD8701 [Cycle 1, 2, 3, 4 on Day 1 and 105 follow up (up to 28 months)]
Minimum concentration (Cmin) of Durvalumab in serum
Change in FOXP3 mRNA expression [From day 1 to day 29]
Percentage change in FOXP3 mRNA expression from pre-treatment (baseline) to post treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 101 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Malignancy treated with curative intent and with no known active disease ≥ 5 years
non-melanoma skin cancer
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:

Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline
Must not have experienced a ≥ Grade 3 imAE or a neurologic or ocular imAE of any grade while receiving prior immunotherapy.
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:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection).
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	La Jolla	California	United States	92093
2	Research Site	Lexington	Kentucky	United States	40536
3	Research Site	Baltimore	Maryland	United States	21287
4	Research Site	Saint Louis	Missouri	United States	63110
5	Research Site	New Brunswick	New Jersey	United States	08901
6	Research Site	Huntersville	North Carolina	United States	28078
7	Research Site	Franklin	Tennessee	United States	37067
8	Research Site	Houston	Texas	United States	77030
9	Research Site	Arlington	Virginia	United States	22205
10	Research Site	Seattle	Washington	United States	98109
11	Research Site	Madison	Wisconsin	United States	53792
12	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
13	Research Site	Toronto	Ontario	Canada	M5G 2M9
14	Research Site	Creteil		France	94010
15	Research Site	Rennes		France	35042
16	Research Site	Toulouse Cedex 09		France	31059
17	Research Site	Villejuif Cedex		France	94805
18	Research Site	Barcelona		Spain	08035
19	Research Site	L'Hospitalet de Llobregat		Spain	08907
20	Research Site	Madrid		Spain	28007
21	Research Site	Madrid		Spain	28027
22	Research Site	Madrid		Spain	28041
23	Research Site	Madrid		Spain	28050