Dose-Expansion Modular Study To Explore the Safety, Tolerability, and Anti-tumor Activity of HER3- DXd Monotherapy and Combinations in Patients With Inoperable Advanced Breast Cancer (ABC) After Progression on T-DXd

NCT06298084 | Recruiting Phase 1 DMC

• 2 other identifiers: 2023-505925-15-002023/3668
• Study Type: interventional
• Target: 152
• Locations: 1 country
• Sites: 1

Brief Summary

ICARUS-BREAST02 is an open-label, multicenter, phase 1b/2, platform study that aims to evaluate the safety, tolerability, and efficacy of HER3-DXd monotherapy and in combination with other anti-cancer agents in patients with ABC. The first 2 modules will evaluate: i. safety and efficacy of HER3-DXd with olaparib in patients with HER2-low and HER2-positive ABC progressed on T-DXd (Module 1) and HER3-DXd monotherapy in patients with HER2-low ABC progressed on T-DXd (Module 0). The main objective of Part 1 is to assess the safety and tolerability of HER3-DXd monotherapy and combination and to determine the recommended phase 2 dose (RP2D) of the combination containing HER3-DXd. The main objective of Part 2 is to assess the efficacy of study therapies in each module based on investigator assessment as evaluated by the objective response rate (ORR) at 6 months.

Conditions

Breast Cancer Metastatic; HER2-positive Metastatic Breast Cancer; HER2 Low Breast Carcinoma; Advanced Breast Cancer

Outcome Measures

Primary Outcomes (11)

• DLTs (dose-limiting toxicity) for part 1a and 1b

  DLTs

  21 months after the beginning of enrolment

• Frequency of safety event for part 1a and 1b

  frequency of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0

  21 months after the beginning of enrolment

• Severity of safety event for part 1a and 1b

  severity of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0

  21 months after the beginning of enrolment

• Proportion of treatment modification due to AEs for part 1a and 1b

  Proportion of treatment discontinuations, interruptions, and dose reductions due to any AEs

  21 months after the beginning of enrolment

• frequency of laboratory abnormalities for part 1a and 1b

  frequency of laboratory abnormalities defined by NCI-CTCAE v5.0 laboratory findings

  21 months after the beginning of enrolment

• Severity of laboratory abnormalities for part 1a and 1b

  Severity of laboratory abnormalities defined by NCI-CTCAE v5.0 laboratory findings

  21 months after the beginning of enrolment

• radiographic changes potentially consistent with ILD/pneumonitis or any other pulmonary signs/symptoms for part 1a and 1b

  Evaluations must include CT (preferably high-resolution CT) and pulmonologist consultation (when the Investigator is not a pulmonologist). Those will be reviewed by an internal multidisciplinary team at GRCC.

  21 months after the beginning of enrolment

• ORR for part 2

  ORR is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators after 6 months of treatment initiation. The objective response will be radiologically assessed every 6 weeks during the first year than every 12 weeks thereafter using RECIST v1.1.

  51 months

• DOR for part 2

  DOR is defined as the time from the date of the first documentation of confirmed response (CR or PR) to the date of the first documentation of progression (PD) or death due to any cause, whichever occurs first. Duration of response will be measured for responding patients (CR or PR) only

  51 months

• PFS for part 2

  PFS is defined as the time from date of first dose until the date of the first objective documentation of disease progression or death from any cause, whichever occurs first. For patients without documented radiological progression, PFS will be censored at the date of last adequate radiological assessment without progression

  51 months

• CBR for part 2

  CBR is defined as the presence of at least a confirmed PR or CR, or a stable disease (SD) ≥ 6 months

  51 months

Secondary Outcomes (15)

• ORR for part 1

  45 months

• DOR for part 1

  45 months

• PFS for part 1

  45 months

• CBR for part 1

  45 months

• PK analysis for part 1

  45 months

Study Arms (3)

Part 1a (safety run-in module 0)

EXPERIMENTAL

Patients with HER2-low ABC who have progressed on T-DXd. Patients in part 1a will receive intravenous infusion of HER3-DXd monotherapy (5.6 mg/kg every 21 days)

Drug: Patritumab deruxtecan

Part 1b (dose finding module 1 + dose expansion module 0)

EXPERIMENTAL

In the dose expansion part, patients will receive the RP2D defined in the dose finding part of different combinations (module 1) and HER3-DXd single agent 5.6 mg/kg IV D1 every 21 days in module 0.

Drug: Patritumab deruxtecan; Drug: Olaparib

Part 2 (dose expansion module 1 + module 0)

EXPERIMENTAL

In the dose expansion part, patients will receive the RP2D defined in the dose finding part of different combinations (module 1) and HER3-DXd single agent 5.6 mg/kg IV D1 every 21 days in module 0.

Drug: Patritumab deruxtecan; Drug: Olaparib

Interventions

Patritumab deruxtecan DRUG

5.6 mg/kg every 21 days

Also known as: U3-1402, HER3-DXd

Part 1a (safety run-in module 0); Part 1b (dose finding module 1 + dose expansion module 0); Part 2 (dose expansion module 1 + module 0)

Olaparib DRUG

100 mg b.i.d PO days 8-14 every 21 days

Also known as: Lynparza

Part 1b (dose finding module 1 + dose expansion module 0); Part 2 (dose expansion module 1 + module 0)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have received prior treatment with T-DXd and presented disease progression while on T-DXd treatment or within 2 months from T-DXd interruption/discontinuation for any reason, without requiring to be the last line of treatment. Patients who have received other lines of treatment after T-DXd and before study entry is capped at 10 patients for each cohort.
• Patients with HER2-positive tumors must have received prior treatment with trastuzumab and taxanes. They may have received prior treatment with T-DM1 and pertuzumab.
• If a patient has a tumor that was previously HR-pos and became HR-neg, prior therapy with CDK4/6 inhibitors is not mandatory.
• Patients with germline pathogenic BRCA1/2 mutations and HER2-positive or HER2-low breast cancer are eligible to the study but must have received a prior treatment with PARP inhibitor (olaparib or talazoparib)
• Female or male patient aged ≥18 years on the day of the ICF signature
• Patient who has histologically confirmed diagnosis of breast cancer with unresectable loco regional or metastatic disease
• Patient must have an ECOG PS ≤1 at the time of screening
• Patients must have HER2-pos (IHC 3+ or IHC2+/ISH positive) or HER-2 low (IHC2+/ISH negative or IHC 1+) tumors with any HR status, any time before T-DXd exposure
• Patient must have at least one radiologically measurable lesion (different from the biopsy site) according to response evaluation criteria in solid tumors (RECIST) V1.1 criteria. At least one predominantly lytic or mixed lytic-blastic bone lesion with identifiable soft tissue component that can be evaluated by Computerized Tomography (CT)/Magnetic Resonance Imaging (MRI) must be present in patients with only bone metastasis
• Patient must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patients must have accepted to perform pre-treatment, on-treatment, and end-of-treatment biopsies
• Patient must have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1, defined per the protocol
• Female patients of reproductive/childbearing potential must have a negative pregnancy test at screening (serum test within 24 hours before C1D1 or urine test within 72 hours of C1D1) and must and must agree to use a highly effective form of contraception or avoid intercourse during and till the end of treatment and for at least 8 months after the last dose of study drug. The following contraception methods are considered highly effective:
• Intrauterine device (IUD)
• Bilateral tubal occlusion
• Vasectomized partner

You may not qualify if:

• Patient with a breast cancer amenable for resection or radiation therapy with curative intent
• Patient with any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have ILD as assessed by imaging during screening
• Patient with clinically severe pulmonary compromise (based on investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
• Any underlying pulmonary disorder (eg, pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion) OR
• Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR
• Prior pneumonectomy
• Patient receiving chronic systemic corticosteroids dosed at \>10 mg/day prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Patients who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study
• Patient with evidence of any leptomeningeal disease
• Patient with clinically significant corneal disease
• Patient with any evidence of severe or uncontrolled systemic diseases (e.g. active bleeding diatheses, active infection, or psychiatric illness) which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required for eligibility
• Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patients must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1
• Inadequate washout period prior to Cycle 1 Day 1, defined as:
• Whole brain radiation therapy or stereotactic brain radiation therapy \<14 days
• Previous treatment with T-DXd \< 28 days
• Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study \<14 days or 5 half-lives, whichever is longer

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead
• Daiichi Sankyo: collaborator

Study Sites (1)

Gustave Roussy Institut

Villejuif, 94805, France

RECRUITING

MeSH Terms

Interventions

patritumab deruxtecan; olaparib

Central Study Contacts

Barbara Pistilli

CONTACT

+33 (0)1 42 11 61 62; barbara.pistilli@gustaveroussy.fr

Fernanda Mosele

CONTACT

+33 (0)1 42 11 61 43; Mariafernanda.MOSELE@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2024
• First Posted: March 7, 2024
• Study Start: March 21, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): June 1, 2029
• Last Updated: March 29, 2024

Record last verified: 2024-03

Locations

FR (1)