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BI 894999 First in Human Dose Finding Study in Advanced Malignancies

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ClinicalTrials.gov Identifier: NCT02516553
Recruitment Status : Recruiting
First Posted : August 6, 2015
Last Update Posted : December 11, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE July 27, 2015
First Posted Date  ICMJE August 6, 2015
Last Update Posted Date December 11, 2019
Actual Study Start Date  ICMJE July 8, 2015
Actual Primary Completion Date April 19, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2019)
  • 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 ]
  • In phase Ia: Number of patients with DLT observed in the first cycle (first 21 days) for Schedules A and B, first 28 days for Schedule C), to meet objective of assessing MTD for each schedule in solid tumour patients & in schedule B in the DLBCL cohort [ Time Frame: Up to 4 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
  • In phase Ia: Number of patients experiencing DLT graded according to the common terminology criteria for adverse events (CTCAE) v.4.03, observed in the first cycle (first 21 days) in order to meet the objective of assessment of the MTD of BI 894999 [ Time Frame: 3 weeks ]
  • 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 ]
Change History Complete list of historical versions of study NCT02516553 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2019)
  • 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 ]
  • efficacy endpoint in phase Ib: Progression-free Survival (PFS) or radiological PFS [ Time Frame: average of 5 months ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Overall survival in patients with NUT Carcinoma (NC) [ Time Frame: Up to 29 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
  • In phase Ia: 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 [ Time Frame: average of 12 months ]
  • efficacy endpoint in both phases Ia and Ib: Objective Response (Complete Response (CR) and Partial Response (PR)) according to RECIST version 1.1 as assessed by the investigator throughout the entire treatment period [ Time Frame: every 6 weeks, average of 4 months ]
  • efficacy endpoint in both phases Ia and Ib: Disease control (CR, PR, stable disease (SD)) according to RECIST version 1.1 as assessed by the investigator throughout the entire treatment period [ Time Frame: every 6 weeks, average of 4 months ]
  • efficacy endpoint in phase Ib: Progression-free Survival (PFS) with tumour assessment every 2 cycles (6 weeks if no delays) during the treatment period and until progression or death is reported [ Time Frame: average of 5 months ]
  • 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 ]
  • In both phases: Cmax(,ss) after single and multiple dose of BI 894999, as measured during the first cycle (3 weeks) [ Time Frame: 3 weeks ]
  • In both phases: AUC0-24 after single and multiple dose of BI 894999, as measured during the first cycle (3 weeks) [ Time Frame: 3 weeks ]
  • In both phases: AUC t after single and multiple dose of BI 894999, as measured during the first cycle (3 weeks) [ Time Frame: 3 weeks ]
  • In both phases: AUC0-8 after single and multiple dose of BI 894999, as measured during the first cycle (3 weeks) [ Time Frame: 3 weeks ]
  • In both phases: t½(,ss) after single and multiple dose of BI 894999, as measured during the first cycle (3 weeks) [ Time Frame: 3 weeks ]
  • In both phases: tmax(,ss) after single and multiple dose of BI 894999, as measured during the first cycle (3 weeks) [ Time Frame: 3 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE BI 894999 First in Human Dose Finding Study in Advanced Malignancies
Official Title  ICMJE 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
Brief Summary

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

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: BI 894999
    day 1 to day 21 in 3-week cycles
  • Drug: BI 894999
    day 1 to day 14 followed by a week off in 3-week cycles in schedule B
  • Drug: BI 894999
    one week on followed by one week off treatment, repeated every two weeks in 4-week cycles
Study Arms  ICMJE
  • Experimental: arm A
    once daily continuous oral intake in 3-week cycles
    Intervention: Drug: BI 894999
  • Experimental: arm B
    once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles
    Intervention: Drug: BI 894999
  • Experimental: arm C
    one week on followed by one week off treatment, repeated every two weeks in 4-week cycles
    Intervention: Drug: BI 894999
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 5, 2019)
176
Original Estimated Enrollment  ICMJE
 (submitted: August 4, 2015)
106
Estimated Study Completion Date  ICMJE May 20, 2021
Actual Primary Completion Date April 19, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

  • Age 18 years or older at the time of signature of the informed consent. For NUT carcinoma (NC) patients, age 15 years or older at the time of signature of the informed consent (in Germany, if NC patients aged 15 to < 18 years are included, their imaging evaluation for the trial will only be with MRI and not with CT scan)
  • 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 NC 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 carcinoma (NC) (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 NC 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 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 (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)
  • Treatment with other investigational drugs or participation in another clinical interventional trial within the past four weeks (past two weeks for NC patients) or within five times the half-life of the previous investigational drug, whichever is the shorter, before start of therapy or concomitant with this trial
  • Systemic anti-cancer therapy within four weeks (past two weeks for NC patients) or five times the half-life of the drug, whichever is shorter. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Boehringer Ingelheim Call Center 1-800-243-0127 clintriage.rdg@boehringer-ingelheim.com
Listed Location Countries  ICMJE Belgium,   France,   Germany,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02516553
Other Study ID Numbers  ICMJE 1367.1
2015-001111-12 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP