BI 894999 First in Human Dose Finding Study in Advanced Malignancies

Inclusion Criteria

• •For all patients
• •Age 18 years or older at the time of signature of the informed consent.
• •Life expectancy of at least 12 weeks after the start of the treatment according to the investigator's judgement
• •Male or female patients. Women of childbearing potential\* 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. For women of childbearing potential using a contraceptive pill, an additional barrier method is necessary due to the potential CYP3A4 inducing effect of BI894999. Male patients having a partner of childbearing potential must use condoms and ensure their partner is using a highly effective method of birth control as described above, during the trial and for at least three months after the end of the trial \* Any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential" as described below.
• •Women not of childbearing potential are defined as: women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
• •\- Written informed consent consistent with ICH-GCP and local legislation
• •For patients with solid tumours
• •Patients with a histologically or cytologically confirmed diagnosis of an advanced unresectable and/or metastatic, malignant solid tumour, who have failed conventional treatment or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies
• •Age ≥ legal age to be adult for the given country at the time of signature of the informed consent. For NC patients, age 15 years or older at the time of signature of the informed consent ( in Germany and South Korea, only legally adult patients may be included
• •Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 or 1 at the time of screening. A score of 2 is allowed for NUT carcinoma patients
• •Recovery of therapy-related toxicities from previous chemotherapy, tyrosine kinase inhibitors, hormone therapy, immunotherapy, antibodies, vaccine therapy, or radiotherapy to CTCAE ≤ grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2)
• •Life expectancy of at least 12 weeks after the start of the treatment according to the investigator's judgement
• •Male or female patients. Women of childbearing potential\* 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. For women of childbearing potential using a contraceptive pill, an additional barrier method is necessary due to the potential CYP3A4 inducing effect of BI894999. Male patients having a partner of childbearing potential must use condoms and ensure their partner is using a highly effective method of birth control as described above, during the trial and for at least three months after the end of the trial treatment
• •Written informed consent consistent with ICH-GCP and local legislation. For adolescent NC patients aged 15 years to \< legal adult age, written assent of the patient and written informed consent of the parents (both or one according to national regulation) or legal guardian of the adolescent
• •Written informed consent for tumour biopsies in the escalation phase Ia
• •* Optional for those patients until extension of the MTD cohort,
• •* Optional for the patients in the extension of MTD cohort at the same time points as described below for the expansion phase. For these patients in the extension of the MTD cohort, if they have an accessible lesion for biopsy, they will be offered optional consent for tumour biopsies
• •In addition, all patients included in the expansion Phase Ib must:
• •Have been diagnosed with one of the four types of tumours selected:
• •* small cell lung cancer (SCLC)
• •* metastatic castrate resistant prostate cancer (mCRPC)
• •* colorectal cancer (CRC)
• •* NUT carcinoma (NC) (for which the "midline" origin is not a prerequisite)
• •Have failed conventional treatments or who are not amenable to standard therapies (per criterion 1) that specifically include for:
• •* SCLC: a platinum-based therapy (previous treatment with topotecan is not mandatory)
• •* mCRPC: a hormonal agent (abiraterone, enzalutamide, or apalutamide) and a taxane (docetaxel or cabazitaxel)
• •* CRC: fluoropyrimidine, oxaliplatin and irinotecan, bevacizumab for patients eligible to this treatment and an anti-epidermal growth factor receptor (EGFR) in RAS (Rat Sarcoma Virus) wild type metastatic CRC.
• •Have a tumour lesion accessible for biopsies (pre- and at steady state under treatment in Cycle 1, ideally from the same anatomic lesion) (except for mCRPC patients having only bone metastases or for patients with therapeutic INR because of treatment with a vitamin K antagonist or a novel oral anticoagulant. Biopsies are optional for NC patients
• •Give written informed consent for two tumour biopsies, one at screening and one after start of treatment, between Day 8 and Day 11 of Cycle 1 (or between day 3 and day 8 if the day of biopsy in Cycle 1 needs to be moved as explained in Section 3.1) (when applicable)
• •In addition, all patients in the mCRPC expansion cohort of Phase Ib must have:
• •Histologically or cytologically confirmed adenocarcinoma of the prostate
• •Radiographic evidence of metastatic prostate cancer (stage M1 or D2). Distant metastases evaluable by bone scan, CT scan, or MRI within 28 days before the start of study treatment.
• •PSA ≥ 5 ng/mL (if no measurable disease by RECIST 1.1)
• •Prior surgical or chemical castration with a serum testosterone of \<50 ng/dL (\< 1.7 nmol/L) by luteinizing hormone releasing level hormone (LHRH) agonist or antagonist, or by abiraterone or by enzalutamide or apalutamide. If the actual method of castration is LHRH agonist or antagonist, the patient must be willing to continue the use of LHRH agonist or antagonist during protocol treatment.
• •Progressive disease defined as at least one of the following:
• •* Progressive measurable disease: using conventional solid tumour criteria RECIST 1.1
• •* Bone scan progression: at least two new lesions on bone scan plus a rising PSA as described in point c below
• •* Increasing PSA level: at least two consecutive rising PSA values over a reference value (PSA no.1) taken at least 1 week apart. A third PSA (PSA no. 3) is required to be \> than PSA no. 2; if not, a fourth PSA (PSA no. 4) is required to be \> to PSA no. 2
• •In patients with DLBCL
• •Patients with histologically confirmed DLBCL who have failed 2 or more lines of systemic therapy including an anti-CD-20 therapy and an anthracycline or who are not amenable to standard therapies but have an indication for therapy as per investigator's judgement. Standard therapies may also include but are not limited to CAR-T cells therapy, depending on approved therapies in the country where the patient is treated
• •ECOG Performance Status 0, 1 or 2 at the time of screening
• •Measurable disease (radiated lesions do not qualify as target lesions) according to according to RECIL 2017 on the CT scan part of the FDG/PET-CT scan
• •Recovery of therapy-related toxicities from previous anti-lymphoma therapy to CTCAE \<= grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2)
• •written informed consent for tumour biopsies (optional)