Clinical Trials /

BI 894999 First in Human Dose Finding Study in Advanced Malignancies

NCT02516553

Description:

The aim of the phase Ia (dose escalation) part of this trial is to assess-> determine the Maximum Tolerated Dose (MTD) using a continuous dosing schedule A, using an intermittent Schedule B (2 weeks on, one week off in 3-week cycles) and the MTD using an intermittent Schedule C (one week on followed by one week off treatment, repeated every two weeks in 4-week cycles) in patients with solid tumours. In the phase Ib expansion part, the aim is to further evaluate the safety profile of BI 894999 at the dose recommended by the data monitoring committee (DMC). Once the MTD has been determined for both schedules A and B in patients with solid tumours, the MTD will be determined as well in patients with diffuse large B-cell lymphoma (DLBCL), using the DMC recommended schedule for solid tumours

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: BI 894999 First in Human Dose Finding Study in Advanced Malignancies
  • Official Title: An Open Label, Phase Ia/Ib Dose Finding Study With BI 894999 Orally Administered Once a Day in Patients With Advanced Malignancies, With Repeated Administration in Patients With Clinical Benefit

Clinical Trial IDs

  • ORG STUDY ID: 1367.1
  • SECONDARY ID: 2015-001111-12
  • NCT ID: NCT02516553

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
BI 894999arm A
BI 894999arm B
BI 894999arm C

Purpose

The aim of the phase Ia (dose escalation) part of this trial is to assess-> determine the Maximum Tolerated Dose (MTD) using a continuous dosing schedule A, using an intermittent Schedule B (2 weeks on, one week off in 3-week cycles) and the MTD using an intermittent Schedule C (one week on followed by one week off treatment, repeated every two weeks in 4-week cycles) in patients with solid tumours. In the phase Ib expansion part, the aim is to further evaluate the safety profile of BI 894999 at the dose recommended by the data monitoring committee (DMC). Once the MTD has been determined for both schedules A and B in patients with solid tumours, the MTD will be determined as well in patients with diffuse large B-cell lymphoma (DLBCL), using the DMC recommended schedule for solid tumours

Trial Arms

NameTypeDescriptionInterventions
arm AExperimentalonce daily continuous oral intake in 3-week cycles
  • BI 894999
arm BExperimentalonce daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles
  • BI 894999
arm CExperimentalone week on followed by one week off treatment, repeated every two weeks in 4-week cycles
  • BI 894999

Eligibility Criteria

        Inclusion criteria:

        For all patients

          -  Age 18 years or older at the time of signature of the informed consent. For NUT
             Midline Carcinoma (NMC) patients, age 15 years or older at the time of signature of
             the informed consent (not applicable for Germany where only patients older than 18
             years will be included)

          -  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 solid tumour, who have failed conventional treatment or
             for whom no therapy of proven efficacy exists, or who are not amenable to standard
             therapies

          -  Eastern Cooperative Oncology Group performance score 0 or 1 at the time of screening

          -  Recovery of therapy-related toxicities from previous chemotherapy, tyrosine kinase
             inhibitors, hormone therapy, immunotherapy, antibodies, vaccine therapy, or
             radiotherapy to CTCAE < or =grade 1 (with the exception of alopecia, peripheral
             sensory neuropathy grade 2)

          -  Written informed consent consistent with ICH-GCP and local legislation. For adolescent
             NMC patients aged 15 to < 18 years 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

               -  optional for those patients until extension of the MTD cohort,

               -  or 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 (part 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) or NUT-midline carcinoma (NMC) (for which the "midline" origin is not a
             prerequisite)

          -  Have a measurable disease (radiated lesions and lesions used for biopsy do not qualify
             as target lesions), according to RECIST 1.1 (R09-0262) (for NMC patients only
             non-measurable disease is acceptable); or according to PCWG3 (R17-3377) for the mCRPC
             cohort

          -  have progressive disease within the last 6 months, according to RECIST 1.1 according
             to PCWG3 for the mCRPC cohort

          -  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 NMC
             patients)

          -  give written informed consent to tumour biopsies, one at screening and one after start
             of treatment, between Day 11 and Day 14 of Cycle 1 (when applicable)

        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)

          -  Further inclusion criteria apply

        Exclusion criteria:

        For all patients:

          -  Inability to swallow tablets

          -  Second malignancy currently requiring another anti-cancer therapy

          -  Serum creatinine greater than 1.5 mg/dL (>132 µmol/L, SI unit equivalent)

          -  Women who are pregnant, nursing, or who plan to become pregnant while in the trial

          -  Treatment with other investigational drugs or participation in another clinical
             interventional trial within the past four weeks or within five times the half-life of
             the previous investigational drug, whichever is shorter, before start of therapy or
             concomitant with this trial

          -  Patients unable to comply with the protocol

          -  Patients who are actively abusing alcohol or drugs. Since no alcohol or drug testing
             is required per protocol, it is at the investigator's discretion to determine abuse.

        For patients with solid tumours:

          -  Additional other serious illness , concomitant non-oncological disease (e.g. active
             infectious disease or known chronic Hepatitis B/Hepatitis C infection and HIV), or
             ongoing toxicity from prior therapies considered by the investigator to potentially
             compromise patient's safety in this trial

          -  History or presence of cardiovascular abnormalities deemed clinically relevant by the
             investigator such as uncontrolled hypertension, congestive heart failure NYHA
             classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial
             infarction within 6 months prior to study entry.Left Ventricular Ejection Fraction
             (LVEF) less than 50% at baseline

          -  Clinical evidence of symptomatic progressive brain or leptomeningeal disease during
             the last 28 days before the start of treatment with BI 894999

          -  Absolute neutrophil count less than 1500/mm^3

          -  Platelet count less than 100 000/mm^3

          -  Bilirubin greater than 1.5 mg/dL (>26 µmol/L, SI unit equivalent) (except known
             Gilbert's syndrome, accepted up to 2 mg/dL or up to 34.2 µmol/L in this case)

          -  Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) greater than
             2.5 times the upper limit of normal (if related to liver metastases, greater than five
             times the upper limit of normal)

          -  Systemic anti-cancer therapy within four weeks or five times the half-life of the
             drug, whichever is shorter (for NMC patients, washout for monoclonal antibodies must
             be discussed with the sponsor). Radiotherapy given for curative intent or other than
             palliative radiotherapy within the past four weeks before start of therapy or
             concomitantly with this trial. This These restrictions does not apply to LHRH agonists
             or antagonists, steroids (given at a stable dose in the last four weeks) used for
             palliative intent, bisphosphonates, and denosumab and to palliative radiotherapy (no
             wash out required)

        For patients with DLBCL:

          -  Patient is eligible for curative salvage high dose therapy followed by stem cell
             transplant.

          -  Primary central nervous system (CNS) lymphoma or known CNS involvement

          -  Prior allogeneic bone marrow or stem cell transplant

          -  High-dose therapy with stem cell support <3 months prior to visit 1

          -  AST or ALT >2.5 x upper limit of normal (CTCAE grade 2 or higher)

          -  Total bilirubin >1.5 x upper limit of normal (CTCAE grade 2 or higher)

          -  Absolute neutrophil count <1.0 x 10^9/L(without growth factor support)

          -  Platelets <100 x 10^9/L (without transfusions)

          -  Significant concurrent medical disease or condition which according to the
             investigator's judgement would either compromise patient safety or interfere with the
             evaluation of the safety of the test drug, e.g. symptomatic congestive heart failure,
             unstable angina pectoris, myocardial infarction within 6 months prior to study entry,
             cardiac arrhythmia requiring therapy with the exception of extra systoles or minor
             conduction abnormalities

          -  Chronic or ongoing infection requiring treatment at the time of enrolment or within
             the previous two weeks, e.g. active infectious disease or known Hepatitis B/Hepatitis
             C infection, HIV

          -  Systemic anti-DLBCL therapy within the past two weeks or five times the half-life of
             the drug, whichever is shorter (palliative radiotherapy and agents used for palliative
             reasons for example steroids and bisphosphonates, are allowed)

          -  Further exclusion criteria apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:In phase Ib: Number of patients experiencing DLTs from start of treatment until end of treatment (in all cycles) as assessed approximately every 3 weeks after Cycle 2 (at the end of each new cycle) in order to determine the recommended phase II dose
Time Frame:average of 12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:efficacy endpoint in phases Ia and Ib: Objective response (OR), defined as CR or PR with tumour assessment during treatment period for each schedule
Time Frame:every 6 weeks, average of 4 months
Safety Issue:
Description:
Measure:efficacy endpoint in phase Ib: Progression-free Survival (PFS) or radiological PFS
Time Frame:average of 5 months
Safety Issue:
Description:
Measure:efficacy endpoint in phase Ib: Best overall response with an evaluation of approximately every 2 cycles (6 weeks if no delays) during the entire treatment period
Time Frame:every 6 weeks, average of 4 months
Safety Issue:
Description:
Measure:In both phases: Cmax,ss after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Time Frame:up to 4 weeks
Safety Issue:
Description:
Measure:In both phases: AUC0-24 after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Time Frame:up to 4 weeks
Safety Issue:
Description:
Measure:In both phases: AUC tau, ss after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Time Frame:up to 4 weeks
Safety Issue:
Description:
Measure:Phase Ia: Number of patients experiencing DLTs from start of treatment until end of treatment (in all cycles) for each of the schedules (A, B and C) in patients with solid tumours and in schedule B in the DLBCL cohort
Time Frame:average of 12 months
Safety Issue:
Description:
Measure:In both phases: Cmax after single dose and at steady state, as measured during the first cycle (3 weeks) for Schedules A and B, the first 4 weeks for Schedule C)
Time Frame:up to 4 weeks
Safety Issue:
Description:
Measure:efficacy endpoint in phase Ib: Prostate Specific Antigen (PSA) response (decline in PSA value ≥50% from baseline) in patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)
Time Frame:average of 12 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Boehringer Ingelheim

Trial Keywords

  • NUT midline carcinoma

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