A study to find a safe and effective dose of BI 1701963 alone and in combination with BI 3011441 in patients with advanced cancer and a certain mutation (Kirsten rat sarcoma viral oncogene homologue [KRAS])

JRCT ID: jRCT2031200385

Registered date:01/03/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: KRAS mutation positive solid tumours (Parts A and B), KRAS mutation positive NSCLC and CRC (Parts C
• Date of first enrollment: 30/04/2021
• Target sample size: 124
• Countries of recruitment: Taiwan,Japan,Korea,Japan
• Study type: Interventional

Intervention(s)

BI 1701963 and BI 3011441 (Part B, C and D).

Part A:
- BI 1701963: starting dose of 400 mg once daily

Part B, C and D:
- BI 1701963:starting dose MTD-1* once daily
- BI 3011441:4 mg/daily
*MTD-1: one dose level below MTD or highest dose established as safe in Part A

Outcome(s)

Primary Outcome

Dose escalation - monotherapy (Part A) and combination therapy (Part B)
-Number of patients with dose-limiting toxicities (DLTs) in the Maximum tolerated dose (MTD) evaluation period
Dose confirmation (Part C) and expansion (Part D) - combination therapy
-Objective response (OR) defined as best overall response of confirmed complete response (CR) or confirmed partial response (PR). Best overall response is defined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 as assessed by the investigator and will consider all tumour assessments from first administration until disease progression or death (whichever occurs first) or last evaluable tumour assessment before start of subsequent anticancer therapy, loss to follow-up or withdrawal of consent.

Secondary Outcome

Dose escalation - monotherapy (Part A) and combination therapy (Part B)
-Cmax of BI 1701963 after the first dose
-AUC0-tz of BI 1701963 after the first dose
-Cmax,ss of BI 1701963 after multiple doses
-AUCt,ss of BI 1701963 after multiple doses
-Cmax of BI 3011441 after the first dose (Part B only)
-AUC0-tz of BI 3011441 after the first dose (Part B only)
-Cmax,ss of BI 3011441 after multiple doses (Part B only)
-AUCt,ss of BI 3011441 after multiple doses (Part B only)

Dose confirmation (Part C) and expansion (Part D) - combination therapy
-Number of patients with Grade >=3 treatment-related adverse events observed during the on-treatment period
-Cmax of BI 1701963 after the first dose
-AUC0-tz of BI 1701963 after the first dose
-Cmax,ss of BI 1701963 after multiple doses
-AUCt,ss of BI 1701963 after multiple doses
-Cmax of BI 3011441 after the first dose
-AUC0-tz of BI 3011441 after the first dose
-Cmax,ss of BI 3011441 after multiple doses
-AUCt,ss of BI 3011441 after multiple doses
-Duration of OR is defined as the time from first documented CR or PR until disease progression or death (whichever occurs first) among patients with OR.
-Tumour shrinkage (in millimetres) is defined as the difference between the minimum post-baseline sum of diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions) and the baseline sum of longest diameters of the same set of target lesions.
-Progression-free survival (PFS) rate at 6 months based on PFS defined as the time from first administration until tumour progression according to RECIST 1.1 or death from any cause, whichever occurs earlier

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

All parts
1.Previously-identified activating KRAS mutation in tumour tissue prior to screening. Activating mutations may include but are not limited to: KRAS mutations in exon 2 (G12, G13), exon 3 (A59, Q61) and exon 4 (K117, A146). See Table 10.2: 3 for a list of alleles. An exemplary list of tests used for historical local determination of KRAS mutation status in international or country-specific certified laboratory (e.g. CAP/CLISA or ISO) is summarized in Table 10.2: 4.
2.Provision of archival tumour tissue, if available, to confirm retrospectively KRAS mutation status and for biomarker assessment
3.At least one target lesion that can be measured per RECIST version 1.1. In patients who only have one target lesion, and a biopsy of the lesion is required, the baseline imaging must be performed at the earliest two weeks after the biopsy.
4.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening
5.Adequate organ function at screening as follows:
a)Absolute neutrophil count (ANC)>=1.5x109/L; hemoglobin>=9.0 g/dL;platelets>=100x109/L without the use of haematopoietic growth factors
b)Total bilirubin =<1.5 times the upper limit of normal (ULN), or=<4xULN for patients who are known to have gilberts syndrome.
c)Creatinine =<1.5xULN. If creatinine is >1.5xULN, patient is eligible if concurrent glomerular filtration rate (GFR)>=50 mL/min (measured or calculated by CKD-EPI formula).
d)Aspartate transaminase (AST) and alanine transaminase (ALT)=<3 x ULN if no demonstrable liver metastases, or =< 5xULN if transaminase elevation is attributable to liver metastases.
6.Age >=18 years of age, or over the legal age of consent as required by local legislation at informed consent.
7.Recovery from any previous therapy related toxicity to Common Terminology Criteria for Adverse Events (CTCAE) Grade =<1 at Cycle 1 Day 1 (except for alopecia, stable sensory neuropathy must be CTCAE Grade =<2) before the first dose.
8.Signed and dated written informed consent in accordance with GCP and local legislation prior to admission to the trial
9.Male or female patients. Women of childbearing potential (WOCBP) and men 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, prior to trial entry and for the duration of trial participation and for a minimum time period after treatment has ended, i.e. at least 4 months for BI 1701963 monotherapy and combination treatment with BI 3011441
10.Women of childbearing potential1 who are not surgically sterilized must have a negative serum pregnancy test completed during the Screening period
Monotherapy and combination therapy dose escalation (Parts A and B)
11.Willingness to undergo pre- and on-treatment tumour biopsies for pharmacodynamics and biomarker assessment. Patients can be enrolled without tumour biopsy upon agreement between the investigator and the sponsor if tumour biopsy is clinically contraindicated.
12.Documented disease progression despite appropriate prior standard therapies2 or for whom no standard therapy exists for their tumour type and disease stage
Combination therapy dose confirmation and expansion part (Parts C1 and D1)
13.Pathologically confirmed diagnosis of locally advanced (stage IIIB/C) or metastatic (stage IVA/B) adenocarcinoma of the lung. Patients must have progressed after having received at least two lines of standard therapy (must have received both chemotherapy and an anti-PD(L)-1 antibody).
Combination therapy dose confirmation and expansion part (Parts C2 and D2)
14.Pathologically confirmed locally advanced or metastatic CRC. Patients must have received all standard treatments appropriate for their tumor type and stage including chemotherapy (fluoropyrimidine,-oxaliplatin and -irinotecan-based chemotherapy). Patients with dMMR/MSI-high CRC must have been previously treated with an anti-PD-1 antibody.

Exclude criteria

All parts
1.Previous anticancer chemotherapy or anticancer immunotherapy within 3 weeks of the first administration of trial drug. Previous anticancer hormonal treatment within 2 weeks of the first administration of trial drugs.
2.Previous treatment with RAS, MAPK or SOS1 targeting agents
3.Radiotherapy within 4 weeks prior to start of treatment except as follows
-Palliative radiotherapy to regions other than the chest is allowed up to 2 weeks prior to start of treatment
-Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior to start of treatment may be allowed but must be discussed with the sponsor.
4.Major surgery (major according to the investigator assessment) performed within 4 weeks prior to start of treatment or planned during the projected course of the trial, e.g. hip replacement.
5.Previous treatment with any investigational agent(s) or targeted treatment within 28 days prior to start of treatment.
6.Known history of hypersensitivity to any of the excipients of BI 1701963 tablets
7.History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of >=3, unstable angina or poorly controlled arrhythmia which are considered clinically relevant by the investigator; myocardial infarction within 6 months prior to start of treatment. Uncontrolled hypertension is defined as: Blood pressure measured in a rested and relaxed condition, where systolic BP >=140 mmHg, or diastolic BP >=90 mmHg, with or without medication.
8.Left ventricular ejection fraction (LVEF)<50%
9.Congenital long QT prolongation syndrome or mean resting corrected QT interval (QTcF)>470 msec at screening.
10.Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patients ability to comply with the trial or interfere with the evaluation of the efficacy and safety of the trial medications.
11.Previous or concomitant malignancies at other sites, except effectively treated
-Non-melanoma skin cancers
-Carcinoma in situ of the cervix
-Ductal carcinoma in situ
-Other malignancy that has been in remission for more than 3 years and is considered to be cured.
12.Leptomeningeal carcinomatosis.
13.Presence or history of uncontrolled or symptomatic brain metastases, unless considered stable by the investigator and local therapy was completed. Use of corticosteroids is allowed if the dose was stable for at least 4 weeks. Inclusion of patients with newly identified brain metastasis/es at screening will be allowed if patients are asymptomatic.
-Patients who have resected brain metastases, or have received radiation therapy that finished at least 4 weeks (whole brain radiation) or 2 weeks (stereotactic body radiotherapy) prior to treatment of the trial are considered eligible if they meet all of the following criteria:
a) Residual neurological symptoms CTCAE Grade=<2
b) Are taking stable doses of dexamethasone, if applicable
c) Follow-up magnetic resonance imaging (MRI) shows no new lesions.
14.History (including current) of interstitial lung disease.
15.Known active hepatitis B infection (defined as presence of Hepatisis B surface antigen (HBs-Ag) and IgM anti-HBc, with or without HBeAg in acute hepatitis, and persistence of HBsAg for at least 6 months, with or without concurrent HBeAg in chronic hepatitis); active hepatitis C infection (defined as presence of Hep C RNA); and/or known HIV carrier.
16.Active infectious disease which puts the patient at increased risk in the opinion of the investigator

Related Information

• Primary Sponsor: WU HAOYU
• Secondary ID(s): NCT04835714