Beamion BCGC-1: A study to find a suitable dose of zongertinib used alone and in combination with other treatments to test whether it helps people with different types of HER2+ cancer that has spread

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Boehringer Ingelheim International GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Aug 2024 → ongoing

Decision date (initial)

2024-06-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Boehringer Ingelheim International GmbH

External identifiers

EU CT number

2023-509566-38-00

WHO UTN

U1111-1297-6046

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Pharmacogenetic, Therapy, Pharmacokinetic, Pharmacodynamic, Safety

Dose escalation (Phase Ib)

• To characterize the safety, tolerability, and the dose-toxicity curve of zongertinib:
o in combination with T-DM1 in patients with HER2+ mBC (Cohort A)
o in combination with T-DXd in patients with HER2+ mBC (Cohort B)
o in combination with T-DXd in patients with mGEAC (Cohort C)
o in combination with capecitabine and trastuzumab in patients with HER2+ mBC (Cohort G)
o in combination with trastuzumab in patients with HER2+ mBC (Cohort K)
o in combination with mFOLFOX6 in patients with HER2+ mCRC (Cohort M)
o in combination with trastuzumab and mFOLFOX6 in patients with HER2+ mCRC (Cohort N)
o in combination with zanidatamab in patients with HER2+ mBC (Cohort O)
by assessing escalating dose levels with overdose control to achieve primary objective of determining maximum tolerated doses (MTDs) and/or doses for further development per cohort

• To evaluate number of patients with "redacted as CCI" within MTD evaluation period per dose level. The MTD evaluation period is defined as the first 21 days of the first treatment cycle for Cohorts A, B, C, G, K, and O. The MTD evaluation period is defined as the first 28 days after the first administration of any trial medication for Cohorts M and N. The MTD is to be determined by dose escalation committee (DEC) based on the totality of data. It may be chosen as the highest dose with less than 25% risk of the true DLT rate being equal to or above 33% during MTD evaluation period based on the Bayesian Logistic Regression Model (BLRM) with overdose control (escalation with overdose control [EWOC]) for the trial

• The primary characterization of primary objective will be based on initial dose administered to patient during the MTD evaluation period and the strategy for handling intercurrent events will be a combined composite and principal stratum approach where some intercurrent events are considered as outcome and some define population consisting of patients who are able to adhere to the assigned treatment regimen and trial schedule

Dose optimization and justification (Phase II)

• To assess anti-tumor activity of zongertinib in the following settings to assist in selection of optimal dose for further clinical development:
o in combination with T-DM1 in patients with HER2+ mBC (Cohort D)
o in combination with T-DXd in patients with HER2+ mBC (Cohort E)
o in combination with T-DXd in patients with HER2+ mGEAC (Cohort F)
o in combination with capecitabine and trastuzumab in patients with HER2+ mBC (Cohort H)
o as a monotherapy in patients with HER2+ mBC (Cohort I, I-ext)
o in combination with trastuzumab in patients with HER2+ mBC (Cohort J, J-ext)
o in combination with trastuzumab in patients with HER2+ mCRC (Cohort L, L-ext)

• The primary endpoint is proportion of patients with objective response (OR) by RECIST version 1.1 as assessed by investigator review in the intent-to-treat population

• The summary measure of OR will include all treated patients regardless of breaks from trial treatment but will exclude the effects of any subsequent anti-cancer therapy started before progression

Secondary objectives 3

1. To characterize the pharmacokinetic properties of zongertinib when given as monotherapy or in combination (all trial parts)
2. To further evaluate preliminary efficacy, safety, and risk-benefit profile of zongertinib monotherapy and zongertinib in combination: with trastuzumab with or without capecitabine, with zanidatamab, with mFOLFOX6 with or without trastuzumab, with T-DXd or with T-DM1 (all trial parts)
3. To evaluate patient reported outcomes (PROs) (dose optimization)

Conditions and MedDRA coding

gastroesophageal junction adenocarcinoma

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Researchers can use the following link https://www.clinicalstudies.boehringer-ingelheim.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed “Document Sharing Agreement”. Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined on the website. Time Frame: One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program. Access Criteria: For study documents – upon signing of a ‚Document Sharing Agreement‘. For study data – 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Patients ≥18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the informed consent form (ICF)
2. Cohorts A to K and Cohort O: Documented HER2+ mBC or mGEAC
3. Cohorts L (L-ext), M, and N (mCRC): Documented HER2 overexpression/amplification
4. For dose optimization and justification (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue
5. History of prior treatment lines in palliative setting: - For cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O documented investigator assessed progression; - For cohorts L, L-ext, M and N documented progression or recurrence of disease during or following their latest line of therapy.
6. Presence of at least one measurable lesion according to RECIST 1.1
7. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
8. Adequate organ function based on laboratory values

Exclusion criteria 4

1. Mean resting corrected QT interval (QTcF) >470 msec.
2. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age
3. Ejection fraction <50% or the lower limit of normal of the institutional standard within 28 days prior to randomization
4. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Dose escalation (Phase Ib) Occurrence of DLTs in the MTD evaluation period. The MTD evaluation period is defined as the first 21 days of the first treatment cycle for Cohorts A, B, C, G, K, and O. The MTD evaluation period is defined as the first 28 days after the first administration of any trial medication for Cohorts M and N.
2. Dose optimization and justification (Phase II) Objective response (OR) defined as the best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 from the date of treatment start until the earliest date of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, or treatment discontinuation as assessed by investigator review

Secondary endpoints 8

1. Dose escalation (Phase Ib) OR, as described above
2. Occurrence of DLTs during the entire treatment period
3. Intensive PK sampling (for cycle 2 only): The following PK parameters of zongertinib when given in combination will be evaluated if feasible: o Cmax (SS): maximum measured concentration (at steady state) o AUC0-4h,ss : area under the concentration-time curve over the time interval from 0 to 4h at steady state o AUC0tz,ss: area under the concentration-time curve over the time interval from 0 to the last quantifiable data point at steady state
4. Dose optimization and justification (Phase II) o Progression-free survival (PFS), defined as the time from treatment start until the earliest date of tumor progression according RECIST 1.1 based on investigator review or death from any cause, whichever occurs first
5. Disease control (DC) defined as best overall response of CR or PR or stable disease (SD) where best overall response is defined according to RECIST 1.1 from first treatment administration until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, or treatment discontinuation, as assessed by investigator review
6. Occurrence of treatment-emergent AEs (TEAEs) "redacted for CCI"
7. Sparse PK sampling: The following PK parameters of zongertinib 1 when given as monotherapy or in combination will be evaluated if feasible: o Cmax (ss): maximum measured concentration (at steady state) o AUC0 tz, ss: area under the concentration-time curve over the time interval from 0 to the last quantifiable data point at steady state
8. PROs: PRO-CTCAE (Mouth/throat sores, Taste changes, Decreased appetite, Nausea, Vomiting, Constipation, Diarrhoea, Shortness of breath, Cough, Rash, Skin dryness, Hair loss, Itching, Numbness & Tingling, Fatigue, Nosebleed, Headache); EORTC IL46 (1 item, overall side effect impact); EORTC IL19 (5 items, physical functioning scale of EORTC QLQ-C30). The time frame is from first administration until an individual patient’s end of treatment (EOT).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Boehringer Ingelheim International GmbH

Sponsor organisation

Boehringer Ingelheim International GmbH

Address

Binger Strasse 173

City

Ingelheim Am Rhein

Postcode

55216

Country

Germany

Scientific contact point

Organisation

Boehringer Ingelheim International GmbH

Contact name

CT Disclosure & Data Transparency

Public contact point

Organisation

Boehringer Ingelheim International GmbH

Contact name

CT Disclosure & Data Transparency

Third parties 17

Locations

5 EU/EEA countries · 45 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 172 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications