IRB Study Number 24-1197
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Investigate the safety, tolerability, and pharmacokinetics (PK) of escalating doses of zongertinib (BI 1810631) as monotherapy (administered orally BID or QD) in patients with advanced and/or metastatic solid tumours harbouring HER2 aberrations.
Determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase II Dose (RP2D) of zongertinib (BI 1810631) monotherapy administered orally in any studied regimen.
To assess the anti-tumour activity of zongertinib (BI 1810631) where the primary measure of interest is the proportion of patients with objective response by RECIST 1.1 as assessed by central independent review.
Secondary Objectives
To assess further measures of efficacy via duration of response by central independent review, disease control by central independent review, objective response via RANO-BM by central independent review for patients with CNS lesions at baseline, disease control via RANO-BM by central independent review for patients with CNS lesions at baseline, and progression free survival by central independent review.
To evaluate safety (by determining the number of patients experiencing DLTs during the entire treatment period) and the assessment of patient-reported outcomes.
Inclusion Criteria
3.3.2.1.1 Inclusion criteria for cohort 6
Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic non-haematologic malignancy. Patient must show presence of at least one measurable non-CNS lesion according to RECIST 1.1 and for Phase Ib cohort 4, additionally, presence of at least one measurable brain lesion according to RANO-BM. Note: Patients with asymptomatic (i.e. no clinical (neurological) symptoms) brain lesions are eligible for Phase Ia and cohorts 1, 2, 3, 5 and 6 of Phase Ib and patients with active brain metastases are eligible for cohort 4 and cohort 6 of Phase Ib.
Eastern Cooperative Oncology Group score of 0, 1 or 2 [R01-0787].
Availability and patient willingness to provide a sample of tumour for confirmation of the patient´s HER2 status. This sample can be archival material obtained at any time prior to study enrollment. If no archival tissue is available, this may be acceptable in exceptional cases after written agreement with the sponsor (please refer to Section 5.4.2).
Patient willing and able to comply with the protocol requirements for tumour biopsies (biopsies are optional for Cohort 6 subjects and biopsies from brain metastases are not allowed). See Section 5.4.3 for specific requirements.
Adequate organ function defined as all of the following:
o Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L (≥ 1.5 x 103 /μL) (≥ 1500/mm3 ); haemoglobin ≥ 9.0 g/dL (≥ 90 g/L) (≥ 5.6 mmol/L); platelets ≥ 100 x 109 /L (100 x 103 /μL) (100 x 103 /mm3 ) without the use of hematopoietic growth factors within 4 weeks of start of trial medication.
o Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except for patients with Gilbert’s syndrome: total bilirubin ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN.
o Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min – calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula (Caucasian and Black: [R12-1392], Japanese: [R22-1536], Other races: [R22-1535]).
o Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN if transaminase elevation is attributable to liver metastases.
o Alkaline Phosphatase < 5 x ULN
Recovered from any previous therapy-related toxicity to ≤ CTCAE Grade 1 at start of treatment (except for alopecia, stable sensory neuropathy and hypothyroidism (patients on thyroid replacement therapy) which must be ≤ CTCAE Grade 2).
Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator.
At least 18 years of age at the time of consent or over the legal age of consent in countries where that is greater than 18 years.
Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
Male or female patients. Women of childbearing potential (WOCBP) 1 and men who are able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information and in Section 4.2.2.3 of the Clinical Trial Protocol.
Inclusion criteria 11 to 23 are not applicable to cohort 6.
- Non-squamous NSCLC Patient with documented HER2 mutation in the TKD as per local lab results via tissue and/or liquid biopsy (tissue preferred whenever available) (see Section 6.2.1 for further details). (Patients are not allowed where there is evidence that their HER2 tyrosine kinase domain mutation was not present until disease progression following prior treatment with a targeted inhibitor).
25.Patient who had received, in the advanced/metastatic setting, at least one line of
systemic therapy. Patients with non-squamous NSCLC harboring additionally genomic aberrations for which approved targeted therapy is available as standard of care, such as but not limited to non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS re-arrangement, and BRAF V600E mutation, must have received prior treatment with an approved targeted therapy.
Patient without active brain metastases or patient with active brain metastases who are not eligible for immediate local therapy, as per investigator evaluation
Patient who is not eligible for any other recruiting cohort
3.3.2.1.2 Inclusion criteria for cohort 8
1 Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic non-haematologic malignancy. Patient must show presence of at least one measurable non-CNS lesion according to RECIST 1.1. Note: Patients with asymptomatic (i.e. no clinical (neurological) symptoms) brain lesions are eligible.
- Eastern Cooperative Oncology Group score of 0 or 1[R01-0787].
3 Availability and patient willingness to provide a sample of tumour for confirmation of the patient´s HER2 status. This sample can be archival material obtained at any time prior to study enrollment. If no archival tissue is available, this may be acceptable in exceptional cases after written agreement with the sponsor (please refer to Section 5.4.2).
4 Patient willing and able to comply with the protocol requirements for tumour biopsies (biopsies are optional for cohort 8 subjects and biopsies from brain metastases are not allowed). See Section 5.4.3 for specific requirements.
- Adequate organ function defined as all of the following:
o Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L (≥ 1.5 x 103 /μL) (≥ 1500/mm3); haemoglobin ≥ 9.0 g/dL (≥ 90 g/L) (≥ 5.6 mmol/L); platelets ≥ 100 x 109 /L (100 x 103 /μL) (100 x 103 /mm3) without the use of hematopoietic growth factors within 4 weeks of start of trial medication.
o Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), except for patients with Gilbert’s syndrome: total bilirubin ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN.
o Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min – calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula (Caucasian and Black: [R12-1392], Japanese: [R22-1536], Other races: [R22-1535]).
o Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN if transaminase elevation is attributable to liver metastases.
o Alkaline Phosphatase < 5 x ULN
- Recovered from any previous therapy-related toxicity to ≤ CTCAE Grade 1 at start of treatment (except for alopecia, stable sensory neuropathy and hypothyroidism (patients on thyroid replacement therapy) which must be ≤ CTCAE Grade 2).
7 Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator.
At least 18 years of age at the time of consent or over the legal age of consent in countries where that is greater than 18 years.
Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
10 Male or female patients. Women of childbearing potential (WOCBP)1 and men who are able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information and in Section 4.2.2.3 of the Clinical Trial Protocol.
Treatment naïve for NSCLC (no prior systemic therapy including chemotherapy, immunotherapy or targeted therapy for stage IIIB or IV adenocarcinoma. However, neo or adjuvant chemo, chemoradio or radiotherapy is permitted if at least 6 months has elapsed prior to disease progression).
NSCLC (adenocarcinoma or squamous) patient with documented HER2 mutation in the tyrosine kinase domain (TKD) or non-squamous NSCLC with a documented HER2 mutation in the non tyrosine kinase domain (non TKD) as per local lab results (see Section 6.2.1 for further details). (Patients are not allowed where there is evidence that their HER2 mutation was not present until disease progression following prior treatment with a targeted inhibitor)
Exclusion Criteria
Major surgery (major according to the investigator’s assessment) performed within 4 weeks prior to first trial treatment or planned within 6 months after screening.
Previous or concomitant malignancies other than the one treated in this trial within the last 2 years, except;
a) effectively treated non-melanoma skin cancers
b) effectively treated carcinoma in situ of the cervix
c) effectively treated ductal carcinoma in situ
d) other effectively treated malignancy that is considered cured by local treatment.
Treatment with a systemic anti-cancer therapy or investigational drug within 21 days or 5 half-lives (whichever is shorter) of the first treatment with the study medication.
Patients who must or wish to continue the intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
Use of concomitant medications that are narrow therapeutic index drugs that are substrates of P-gp or BCRP (e.g. digoxin, dabigatran etexilate).
This criteria is no longer applicable following approval of this amended CTP v5
Treatment with strong CYP3A inducers as specified in Section 4.2.2.1.
This criteria is no longer applicable following approval of this amended CTP v4
Previous treatment with zongertinib.
Radiotherapy within 2 weeks prior to first study treatment, except palliative radiotherapy to regions other than the chest, which is allowed up to 1 week prior to first study treatment.
Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the safety and efficacy of the test drug.
History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥ III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction within 6 months prior to first study treatment.
Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block.
Mean resting corrected QT interval (QTcF) >470 msec.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, 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.
Ejection fraction (EF) <50% or the lower limit of normal of the institutional standard.
Women who are pregnant, nursing, or who plan to become pregnant or nurse during the trial or within 30 days after the last dose of trial treatment. However, women who are nursing can be enrolled if they stop nursing. In this case, the patient cannot resume nursing until 30 days from discontinuation of study treatment.
Presence or history of uncontrolled or symptomatic brain and subdural metastases, unless considered stable by the investigator and local therapy was completed (except for Cohort 4 and Cohort 6 in Phase Ib part). Patients with known leptomeningeal disease. Use of corticosteroids is allowed if the dose is decreasing or was stable for at least 1 week. Inclusion of patients with newly identified brain metastasis/es at screening will be allowed if patients are asymptomatic and stable by the investigator and immediate CNS treatment is unlikely to be required.
Patients with chronic HBV infection with active disease who meet the criteria for anti HBV therapy (according to local / institutional standard) who have not been treated with suppressive antiviral therapy prior to initiation of study treatment OR Patients with a history of HCV infection who meet one or both of the following criteria:
i. Currently receiving curative antiviral treatment
ii. HCV viral load is above the limit of quantification (HCV RNA positive)
Known history of allergy to the trial drug, or any excipients of the trial drug.
Active alcohol or drug abuse in the opinion of the investigator that would limit the ability of the patient to comply with the protocol requirements.
Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable trial participant).
Active or known pre-existing or history of non-infectious interstitial lung disease/pneumonitis.
Patients with history of human immunodeficiency virus (HIV) infection who meet one or more of the following criteria;
a. CD4+ count < 350 cells/μL
b. Viral load > 400 copies/μL (local lab assessment)
c. Not receiving antiretroviral therapy
d. Receiving established antiretroviral therapy for less than four weeks prior to the start of study treatment
e. History of AIDS-defining opportunistic infections within 12 months prior to start of study treatment
Patients with a history of HIV who do not meet any of the criteria above are eligible to participate but the patient must be under the care of a HIV/Infectious Diseases specialist or an HIV/Infectious Diseases specialist must be consulted prior to inclusion.
