A Study of Novel Anti-cancer Agents in Patients With Metastatic Triple Negative Breast Cancer

Study Overview
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Brief Summary
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This study is designed to determine the efficacy and safety of durvalumab in combination with novel oncology therapies with or without paclitaxel and durvalumab + paclitaxel for first-line metastatic triple negative breast cancer

Detailed Description
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This is a Phase IB/II, 2-stage, open-label, multicenter study to determine the efficacy and safety of durvalumab in combination with novel oncology therapies (i.e. therapies designed for immune modulation) with or without paclitaxel and durvalumab + paclitaxel as first-line treatment in patients with metastatic triple negative breast cancer (TNBC). The study is designed to concurrently evaluate potential novel treatment combinations with clinical promise using a 2-stage approach. The study will use a Simon 2-Stage design to evaluate which cohorts may proceed to expansion. Part 1 is a Phase IB study of safety and initial efficacy, and Part 2 may expand patient enrollment if adequate efficacy signal is observed in Part 1. The treatment regimens evaluated in Part 2 will depend on the evaluation of safety and efficacy outcomes in Part 1.

Official Title
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A Phase IB/II, 2-stage, Open-label, Multicenter Study to Determine the Efficacy and Safety of Durvalumab (MEDI4736) + Paclitaxel and Durvalumab (MEDI4736) in Combination With Novel Oncology Therapies With or Without Paclitaxel for First-line Metastatic Triple Negative Breast Cancer

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Capivasertib
* Drug: Oleclumab
* Drug: Paclitaxel
* Drug: Trastuzumab deruxtecan
* Drug: Datopotamab deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Female At least 18 years of age at the time of screening Patient must have locally confirmed advanced/unresectable or metastatic TNBC. No prior treatment for metastatic (Stage IV) TNBC Patient must have at least 1 lesion, not previously irradiated, that can be accurately measured WHO/ECOG status at 0 or 1 at enrollment Patients enrolled to Arm 6 (durvalumab and DS-8201a) Must provide documentation of locally determined advanced/unresectable or metastatic TNBC with HER2 low tumor expression (IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) Patients enrolled in Arm 8 (durvalumab + Dato-DXd) Must have PD-L1 positive tumor as determined by an IHC based assay Exclusion criteria History of allogeneic organ transplantation Active or prior documented autoimmune or inflammatory disorders Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies) Untreated CNS metastases Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients Any concurrent chemotherapy, IP, or biologic therapy for cancer treatment Female patients who are pregnant, breastfeeding Cardiac Ejection Fraction less than 50% Patients enrolled in Arm 2 only: Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2C9 or CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort) Diagnosis of diabetes mellitus Type I or diabetes mellitus Type II requiring insulin treatment. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, potential for torsades de pointes, 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 Prior treatment with PI3K inhibitors, AKT inhibitors, or mammalian target of rapamycin (mTOR) inhibitors. Patients enrolled in Arm 5 only: History of venous thromboembolism in the past 3 months Patients enrolled in Arm 7 and 8 only: Clinically significant corneal disease in the opinion of the Investigator. Patients enrolled in Arm 6, 7 and 8 only: History of or active interstitial lung disease/pneumonitis Use of chloroquine or hydroxychloroquine in <14 days prior to Day 1 of DS-8201a (Arm 6) or Dato-DXd (DS-1062a; Arm 7 and 8) treatment Patients enrolled in Arm 6 only: Previously been diagnosed as HER2+ or received HER2-targeted therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1: At least 20 patients in the durvalumab-paclitaxel arm and at least 30 patients in each of the other novel treatment combination arms will be enrolled, for a total of approximately 140 patients (durvalumab + paclitaxel arm and 4 novel treatment combination arms). Additional patients may be enrolled in order to have 20 or 30 evaluable (i.e. dosed) patients per durvalumab - paclitaxel arm or novel treatment combination arm, respectively. Part 2: Approximately 27 patients will be assigned to each treatment arm, for an anticipated total of 57 response-evaluable patients per arm (ie, 30 patients in Part 1 and 27 patients in Part 2 per treatment arm, with the exception of Arm 1, which will enroll 20 patients in Part 1 and will not be expanded to Part 2). Patient expansion from 30 patients in Part 1 to an additional 27 patients from Part 2 will be determined based on a futility analysis utilizing a Simon 2 Stage design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>durvalumab + paclitaxel | Drug: Durvalumab<br>* Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8<br>* Other names: MEDI4736;Drug: Paclitaxel<br>* Paclitaxel iv 4-week cycles: 3 weeks once weekly (q1w) and 1 week off<br>|
| Experimental: Arm 2<br>durvalumab + paclitaxel + capivasertib | Drug: Durvalumab<br>* Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8<br>* Other names: MEDI4736;Drug: Capivasertib<br>* Capivasertib oral bid 4-week cycles; 3 weeks on (dosing on days 2,3,4 and 5) and 1 week off<br>* Other names: AZD5363;Drug: Paclitaxel<br>* Paclitaxel iv 4-week cycles: 3 weeks once weekly (q1w) and 1 week off<br>|
| Experimental: Arm 5<br>durvalumab + paclitaxel + oleclumab | Drug: Durvalumab<br>* Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8<br>* Other names: MEDI4736;Drug: Oleclumab<br>* Oleclumab iv Every 2 weeks (q2w) for first 2 cycles (days 1 and 15 in cycles 1 and 2), then every 4 weeks (q4w) starting at cycle 3 day 1<br>* Other names: MEDI9447;Drug: Paclitaxel<br>* Paclitaxel iv 4-week cycles: 3 weeks once weekly (q1w) and 1 week off<br>|
| Experimental: Arm 6<br>durvalumab + trastuzumab deruxtecan | Drug: Durvalumab<br>* Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8<br>* Other names: MEDI4736;Drug: Trastuzumab deruxtecan<br>* Trastuzumab deruxtecan iv 3-week cycles (once weekly) q3w<br>* Other names: DS-8201a;|
| Experimental: Arm 7<br>durvalumab + datopotamab deruxtecan | Drug: Durvalumab<br>* Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8<br>* Other names: MEDI4736;Drug: Datopotamab deruxtecan<br>* Datopotamab deruxtecan iv 3-week cycles (once weekly) q3w<br>* Other names: Dato-DXd; DS-1062a;|
| Experimental: Arm 8<br>durvalumab + datopotomab deruxtecan (patients with PD-L1 positive status) | Drug: Durvalumab<br>* Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8<br>* Other names: MEDI4736;Drug: Datopotamab deruxtecan<br>* Datopotamab deruxtecan iv 3-week cycles (once weekly) q3w<br>* Other names: Dato-DXd; DS-1062a;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Part 1: Assessment of safety and tolerability of each treatment arm Part 2: Endpoints based on Investigator assessment according to RECIST 1.1: ORR (objective response rate): The percentage of evaluable patients with a confirmed Investigator-assessed visit response of CR (complete response) or PR (partial response). | Part1: From informed consent until the safety follow-up visit 3 months after the last dose of study drug. Part 2: From informed consent until the safety follow-up visit 3 months after the last dose of study drug. | 
| Laboratory findings | Assessment of safety and tolerability of each treatment arm | Part 1: From informed consent until the safety follow-up visit 3 months after the last dose of study drug. Part 2:From informed consent until the safety follow-up visit 3 months after the last dose of study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Assessment of the efficacy of each treatment arm according to RECIST 1.1. ORR: The percentage of evaluable patients with a confirmed Investigator-assessed response of CR (complete response) or PR (partial response) Applicable for Part 1 and Part 2. | Approx. 30 months | 
| Progression-free survival (PFS). | Assessment of the efficacy of each treatment arm according to RECIST 1.1. PFS: Time from date of first dose until the date of objective radiological disease progression or death (by any cause in the absence of progression) Applicable for Part 1 and Part 2 | On-study tumor assessments occur every 8 weeks (Arms 1-5),every 6 weeks (Arms 6-8) until week 48 and then every 12 weeks thereafter until radiological progression, death, withdrawal of consent or study completion up to approx. 30 months | 
| Duration of response (DoR) | Assessment of the efficacy of each treatment arm according to RECIST 1.1. DoR: Time from date of first detection of objective response (which is subsequently confirmed) until the date of objective radiological disease progression Applicable for Part 1 and Part 2 | On-study tumor assessments occur every 8 weeks (Arms 1-5), every 6 weeks (Arms 6-8) until week 48 and then every 12 weeks thereafter until radiological progression, death, withdrawal of consent or study completion up to approx. 30 months | 
| Overall survival (OS) | OS: Time from date of first dose until the date of death by any cause Applicable for Part 1 and Part 2 | Approx. 30 months | 
| Serum concentration of durvalumab and serum or plasma concentration of novel oncology therapies | Assessment of pharmacokinetics (PK) Applicable for Part 1 (Arms 1-8) and for Part 2 (Arm 7) | From cycle 1 day 1 until cycle 7 day 1 (Arms 1-5), from cycle 1 day 1 until cycle 8 day 1 (Arms 6-8) (each cycle is 28 days) and every 12 weeks thereafter until study completion approx. 30 months | 
| Presence of anti-drug antibodies (ADAs) for durvalumab and applicable novel oncology therapies | Investigation of the immunogenicity of durvalumab and novel oncology therapies in all applicable treatment arms Applicable for Part 1 (Arms 1-8) and for Part 2 (Arm 7) | From cycle 1 day 1 until cycle 7 day 1 (Arms 1-5), from cycle 1 day 1 until cycle 8 day 1 (Arms 6-8) (each cycle is 28 days) and every 12 weeks thereafter until study completion approx. 30 months | 
| Progression-free survival (PFS 6) | PFS at 6 months following date of first dose Applicable for Part 2 | On-study tumor assessments occur every 8 weeks until week 48 (Arms 1-5), every 6 weeks until week 48 (Arms 6-8) and then every 12 weeks thereafter until radiological progression, death, withdrawal of consent or study completion up to approx. 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, TNBC, Triple Negative, Triple Negative Breast Cancer, Triple-Negative Breast Cancer, Triple-Negative Breast Neoplasm, ER-Negative PR-Negative HER2-Negative Breast Cancer, ER-Negative PR-Negative HER2-Negative Breast Neoplasms, PD-L1 high TNBC