Clinical trial NCT03742102: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Triple Negative Breast Neoplasms
Keywords: 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
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2018-11-15
Enrollment: 243
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: 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.
measure: Laboratory findings
timeFrame: 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 outcomes:
measure: Objective response rate (ORR)
timeFrame: Approx. 30 months
measure: Progression-free survival (PFS).
timeFrame: 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
measure: Duration of response (DoR)
timeFrame: 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
measure: Overall survival (OS)
timeFrame: Approx. 30 months
measure: Serum concentration of durvalumab and serum or plasma concentration of novel oncology therapies
timeFrame: 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
measure: Presence of anti-drug antibodies (ADAs) for durvalumab and applicable novel oncology therapies
timeFrame: 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
measure: Progression-free survival (PFS 6)
timeFrame: 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
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Research Site
state: Arizona
city: Columbia
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Grand Rapids
country: United States
facility: Research Site
state: Michigan
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Williamsburg
country: United States
facility: Research Site
state: Virginia
city: Kelowna
country: Canada
facility: Research Site
state: British Columbia
city: London
country: Canada
facility: Research Site
state: Ontario
city: Greenfield Park
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Opole
country: Poland
facility: Research Site
city: Rzeszów
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan
country: Taiwan
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Barts Cancer Institute
name: Peter Schmid, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: