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

• ClinicalTrials.gov Identifier: NCT03742102
• Recruitment Status: Recruiting
• First Posted: November 15, 2018
• Last Update Posted: April 24, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: October 25, 2018
• First Posted Date: November 15, 2018
• Last Update Posted Date: April 24, 2024
• Actual Study Start Date: December 21, 2018
• Estimated Primary Completion Date: November 14, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 2, 2023)

• Incidence of adverse events [ Time Frame: 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. ]
  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).
• Laboratory findings [ Time Frame: 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. ]
  Assessment of safety and tolerability of each treatment arm

Original Primary Outcome Measures (submitted: November 14, 2018)

• Incidence of adverse events [ Time Frame: From informed consent until the safety follow-up visit 3 months after the last dose of study drug ]
  Assessment of safety and tolerability of each treatment arm
• Laboratory findings [ Time Frame: From informed consent until the safety follow-up visit 3 months after the last dose of study drug ]
  Assessment of safety and tolerability of each treatment arm

Current Secondary Outcome Measures (submitted: April 28, 2023)

• Objective response rate (ORR) [ Time Frame: Approx. 30 months ]
  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.
• Progression-free survival (PFS). [ Time Frame: 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 ]
  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
• Duration of response (DoR) [ Time Frame: 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 ]
  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
• Overall survival (OS) [ Time Frame: Approx. 30 months ]
  OS: Time from date of first dose until the date of death by any cause Applicable for Part 1 and Part 2
• Serum concentration of durvalumab and serum or plasma concentration of novel oncology therapies [ Time Frame: 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 ]
  Assessment of pharmacokinetics (PK) Applicable for Part 1 (Arms 1-8) and for Part 2 (Arm 7)
• Presence of anti-drug antibodies (ADAs) for durvalumab and applicable novel oncology therapies [ Time Frame: 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 ]
  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)
• Progression-free survival (PFS 6) [ Time Frame: 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 ]
  PFS at 6 months following date of first dose Applicable for Part 2

Original Secondary Outcome Measures (submitted: November 14, 2018)

• Objective response rate (ORR) [ Time Frame: Approximately 24 months ]
  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 or PR
• Progression-free survival (PFS). [ Time Frame: On-study tumor assessments occur every 8 weeks until week 48 and then every 12 weeks thereafter until confirmed radiological progression, death, withdrawal of consent or study completion, up to approximately 24 months ]
  Assessment of the efficacy of each treatment arm according to RECIST 1.1. PFS: Time from date of treatment assignment until the date of objective radiological disease progression or death (by any cause in the absence of progression)
• Duration of response (DoR) [ Time Frame: On-study tumor assessments occur every 8 weeks until week 48 and then every 12 weeks thereafter until confirmed radiological progression, death, withdrawal of consent or study completion, up to approximately 24 months ]
  Assessment of the efficacy of each treatment arm according to RECIST 1.1. DoR: Time from date of first detection of objective response until the date of objective radiological disease progression
• Overall survival (OS) [ Time Frame: Approximately 24 months ]
  OS: Time from date of treatment assignment until the date of death by any cause
• Blood concentration of durvalumab and novel oncology therapies [ Time Frame: From cycle 1 day 1 until cycle 7 day 1 (each cycle is 28 days) and every 12 weeks thereafter until study completion, approximately 24 months ]
  Assessment of pharmacokinetics (PK)
• Presence of anti-drug antibodies (ADAs) for durvalumab and applicable novel oncology therapies [ Time Frame: From cycle 1 day 1 until cycle 7 day 1 (each cycle is 28 days) and every 12 weeks thereafter until study completion, approximately 24 months ]
  Investigation of the immunogenicity of durvalumab and novel oncology therapies in all applicable treatment arms

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Novel Anti-cancer Agents in Patients With Metastatic Triple Negative Breast Cancer
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment

• Condition: Triple Negative Breast Neoplasms

Intervention

• Drug: Durvalumab
  Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8
  Other Name: MEDI4736
• Drug: Capivasertib
  Capivasertib oral bid 4-week cycles; 3 weeks on (dosing on days 2,3,4 and 5) and 1 week off
  Other Name: AZD5363
• Drug: Oleclumab
  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
  Other Name: MEDI9447
• Drug: Paclitaxel
  Paclitaxel iv 4-week cycles: 3 weeks once weekly (q1w) and 1 week off
• Drug: Trastuzumab deruxtecan
  Trastuzumab deruxtecan iv 3-week cycles (once weekly) q3w
  Other Name: DS-8201a
• Drug: Datopotamab deruxtecan
  Datopotamab deruxtecan iv 3-week cycles (once weekly) q3w
  Other Name: Dato-DXd; DS-1062a

Study Arms

• Experimental: Arm 1
  durvalumab + paclitaxel
  Interventions:

  • Drug: Durvalumab
  • Drug: Paclitaxel
• Experimental: Arm 2
  durvalumab + paclitaxel + capivasertib
  Interventions:

  • Drug: Durvalumab
  • Drug: Capivasertib
  • Drug: Paclitaxel
• Experimental: Arm 5
  durvalumab + paclitaxel + oleclumab
  Interventions:

  • Drug: Durvalumab
  • Drug: Oleclumab
  • Drug: Paclitaxel
• Experimental: Arm 6
  durvalumab + trastuzumab deruxtecan
  Interventions:

  • Drug: Durvalumab
  • Drug: Trastuzumab deruxtecan
• Experimental: Arm 7
  durvalumab + datopotamab deruxtecan
  Interventions:

  • Drug: Durvalumab
  • Drug: Datopotamab deruxtecan
• Experimental: Arm 8
  durvalumab + datopotomab deruxtecan (patients with PD-L1 positive status)
  Interventions:

  • Drug: Durvalumab
  • Drug: Datopotamab deruxtecan

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 3, 2023): 240
• Original Estimated Enrollment (submitted: November 14, 2018): 100
• Estimated Study Completion Date: November 14, 2024
• Estimated Primary Completion Date: November 14, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria

1. Female
2. At least 18 years of age at the time of screening
3. Patient must have locally confirmed advanced/unresectable or metastatic TNBC.
4. No prior treatment for metastatic (Stage IV) TNBC
5. Patient must have at least 1 lesion, not previously irradiated, that can be accurately measured
6. 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

1. History of allogeneic organ transplantation
2. Active or prior documented autoimmune or inflammatory disorders
3. 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)
4. Untreated CNS metastases
5. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
6. Any concurrent chemotherapy, IP, or biologic therapy for cancer treatment
7. Female patients who are pregnant, breastfeeding
8. Cardiac Ejection Fraction less than 50%

Patients enrolled in Arm 2 only:

1. 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)
2. Diagnosis of diabetes mellitus Type I or diabetes mellitus Type II requiring insulin treatment.
3. 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
4. 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:

1. History of or active interstitial lung disease/pneumonitis
2. 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
3. Patients enrolled in Arm 6 only: Previously been diagnosed as HER2+ or received HER2-targeted therapy.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

Contact: AZ Breast Cancer Study Navigators AZ Breast Cancer Study Navigators; +1-877-400-4656; AstraZeneca@CareboxHealth.com

• Listed Location Countries: Canada, Korea, Republic of, Poland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03742102
• Other Study ID Numbers: D933LC00001; 2018-000764-29 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• 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 de-identified 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

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Peter Schmid, MD, PhD; Barts Cancer Institute

• PRS Account: AstraZeneca
• Verification Date: April 2024