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This Study Aims to Find the Best Dose of BI 907828 in Patients With Different Types of Advanced Cancer (Solid Tumors)

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ClinicalTrials.gov Identifier: NCT03449381
Recruitment Status : Recruiting
First Posted : February 28, 2018
Last Update Posted : August 7, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:

Phase Ia - The main objective of the dose-escalation part of the trial is to determine the maximum tolerated dose (MTD), based on the frequency of patients experiencing dose limiting toxicities (DLT) during the first treatment cycle, and the recommended dose for expansion (RDE) of BI 907828 monotherapy, and to evaluate its safety and tolerability, by monitoring the occurrence and severity of adverse events (AEs), in two different schedules (Arm A with one single dose every 21 days, Arm B with one single dose on Days 1 and 8, every 28 days).

The secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 907828 monotherapy, and the preliminary assessment of anti-tumor activity in patients with advanced or metastatic solid tumors.

Phase Ib - In the expansion cohorts of the trial, the main objectives are to assess efficacy, and to further assess the safety, and PK profiles at the RDE, and determine the recommended Phase 2 dose (RP2D).


Condition or disease Intervention/treatment Phase
Neoplasms Drug: BI 907828 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ia/Ib, Open Label, Multicenter, Dose-escalation Study of BI 907828 in Patients With Advanced or Metastatic Solid Tumors
Actual Study Start Date : May 21, 2018
Estimated Primary Completion Date : October 27, 2021
Estimated Study Completion Date : January 20, 2023

Arm Intervention/treatment
Experimental: Dose Escalation Drug: BI 907828
Film-coated tablet

Experimental: Dose Expansion Drug: BI 907828
Film-coated tablet




Primary Outcome Measures :
  1. Phase Ia- MTD based on number of patients with DLTs during first treatment cycle [ Time Frame: up to 24 Months ]
  2. Ph Ib - Objective response per RECIST, RANO criteria, or RANO-BM, and assessed by Investigator, measured separately for each cohort, from treatment start until earliest of progression, death, or last tumor assessment and before subsequent therapy [ Time Frame: up to 24 Months ]
  3. Phase Ia - Number of patients with DLTs during first treatment cycle (21 days, Arm A; 28 days, Arm B) [ Time Frame: up to 28 days ]

Secondary Outcome Measures :
  1. Phase Ia- Cmax: maximum measured concentration of BI 907828 in plasma [ Time Frame: up to 24 Months ]
  2. Phase Ia - AUC0-∞: area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity. [ Time Frame: up to 24 Months ]
  3. Phase Ib - Disease control (DC) with tumor assessment until disease progression (according to RECIST v.1.1 for non-brain lesions, or RANO/RANO-BM- criteria for brain lesions) as assessed by the Investigator, or start of subsequent anti-cancer treatment [ Time Frame: up to 24 Months ]
  4. Phase Ib - Progression-free Survival defined from date of start of BI 907828 to earliest of date of disease progression or death (according to RECIST 1.1, RANO/RANO-BM as applicable), as assessed by the Investigator, measured separately for each cohort. [ Time Frame: up to 24 Months ]
  5. Phase Ib - Number of patients with Grade ≥3 treatment-related adverse events observed during the entire treatment period. [ Time Frame: up to 24 Months ]
  6. Phase Ib - Cmax: maximum measured concentration of BI 907828 in plasma [ Time Frame: up to 24 Months ]
  7. Phase Ib - AUC0-∞: area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity [ Time Frame: up to 24 Months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provision of signed and dated, written informed consent form ICF in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses.
  • Pathologically documented, advanced solid tumors.
  • Radiologically documented disease progression or relapse during or after all standard of care treatments. Patients who are not eligible to receive standard of care treatments, and for whom no proven treatments exist, are eligible.
  • Phase Ia (dose escalation) only:

    • Patient has a tumor with either a known TP53 wild type status, or unknown TP53 status, and regardless of MDM2 amplification status, at the time of study entry.

      -- Phase Ib (expansion phase) only:

    • Cohort 1: TP53 wt and MDM2-amplified non-squamous NSCLC
    • Cohort 2: TP53 wt and MDM2-non-amplified non-squamous NSCLC.
    • Cohort 3: TP53 wt and MDM2-amplified soft tissue sarcoma, glioblastoma, and urothelial carcinoma.
    • Cohort 4: TP53 wt and MDM2-amplified solid tumors with brain metastases. Patients may have received any systemic and/or local treatment for their brain lesions but there needs to be unequivocal evidence of progression of at least one brain lesion. Patients on corticosteroids must have a stable dose for at least 5 days prior to baseline magnetic resonance imaging (MRI).
  • Phase Ia (dose escalation) only:

    • Patient with either measurable or non-measurable disease.
    • Non-evaluable disease allowed.

      -- Phase Ib (expansion phase) only:

    • At least one target lesion that can be accurately measured per RECIST v.1.1.
    • For glioblastoma: measurable disease by RANO criteria (bidimensional contrast-enhancing lesions with clearly defined margins by MRI, with 2 perpendicular diameters of at least 10 mm, visible on two or more 2 axial slices). Patients on corticosteroids must have a stable dose for at least 5 days prior to baseline MRI.
  • Patient must be willing to submit the blood sampling for the PK, PD, biomarker, and PGx analyses.
  • Availability and willingness to provide a fresh tumor tissue sample obtained after relapse or progression during or after prior therapy. In case a fresh biopsy cannot be obtained (e.g. inaccessible lesions or patient safety concern), an archived specimen, collected before screening, may be submitted.
  • Male or female ≥18 years old (for Japan, ≥20 years old) at the time of signature of the ICF
  • ECOG performance status of 0 or 1 (an ECOG of 2 is acceptable, if it is due to noncancer- related disability, and after agreement with Sponsor).
  • Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement.
  • Adequate organ function
  • Male or female patients. Women of childbearing potential (WOCBP, defined as female patients who are premenopausal or who had no cessation of menses within 12 months without an alternative medical cause, but not including female patients who are permanently sterilized) and men able to father a child must be ready and able to use two 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 beginning at screening, during trial participation and until 35 days and 3 months, respectively for women and men, after trial completion (i.e. after the last administration of trial medication). A list of contraception methods meeting these criteria is provided in the patient information.

Exclusion Criteria:

  • Previous administration of BI 907828 or any other TP53-MDM2 or TP53-MDMX (MDM4) antagonist.
  • Patient has a tumor with a documented mutation in the TP53 gene determined previously or at screening irrespective of MDM2 amplification status. For dose escalation part only, patients who have tumors with unknown TP53 and/or MDM2 status at the time of screening are eligible at investigator's discretion.
  • Active or untreated brain metastases from non-brain tumors, except for expansion cohort 4 (solid tumors with brain metastases); Note: Patients with previously treated brain metastases may participate provided they are stable, without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or computed tomography (CT) scan), for at least four weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline; have no evidence of new or enlarging brain metastases. Patients on corticosteroids must have a stable dose for at least 5 days prior to baseline MRI.
  • Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors. Note: Low molecular weight heparin and prophylactic low dose warfarin are permitted; PT/PTT must meet the inclusion criteria; patients taking low dose warfarin must have their INR followed according to institutional guidelines.
  • Patients with history of bleeding diathesis.
  • Major surgery (major according to the Investigator's assessment) performed within 12 weeks prior to start of study treatment, or planned within 12 months after screening (e.g. hip replacement).
  • Any other documented active or suspected malignancy or history of malignancy within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix, or other local tumors considered cured by local treatment.
  • Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
  • Currently enrolled in another investigational device or drug trial, or less than 30 days since receiving other investigational treatments. Patients who are in followup/ observation for another clinical trial are eligible.
  • Patients who have been treated with any other anticancer drug other than antibodies within 4 weeks or within 5 half-life periods (whichever come earlier) prior to first administration of BI 907828. For patients who have been previously treated with antibodies, within approximately 3 half-life periods prior to first administration of BI 907828.
  • Persistent toxicity from previous treatments that has not resolved to ≤ CTCAE Grade 1 (except for alopecia and CTCAE Grade 2 neuropathy, or asthenia/fatigue).
  • Known human immunodeficiency virus (HIV) infection, acute or chronic viral hepatitis. Patients with a history of hepatitis B virus infection, irrespective of their reactivation risk status, should also be excluded. The testing at screening is not mandatory and left at the discretion of investigator.
  • Known hypersensitivity to the trial drug or its excipients.
  • Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the Investigator, would make the patient inappropriate for entry into the trial.
  • Chronic alcohol or drug abuse or any condition that, in the Investigator's opinion, makes them an unreliable trial patient or unlikely to complete the trial.
  • Women who are pregnant, nursing, or who plan to become pregnant while in the trial; female patients who do not agree to the interruption of breast feeding from the start of study treatment to within 30 days after the last study treatment.
  • Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) >470 msec
    • 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
    • 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. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the patient's cardiac disease has not significantly worsened since this measurement in the opinion of the Investigator or of the treating physician or both.
  • Use of concomitant medications that are narrow therapeutic index drugs that are substrates of P-gp or BCRP (e.g. digoxin, dabigatran, etexilate).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03449381


Contacts
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Contact: Boehringer Ingelheim 1-800-243-0127 clintriage.rdg@boehringer-ingelheim.com

Locations
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United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06511
Contact: Patricia LoRusso    +001 (203) 785-5944    Patricia.lorusso@yale.edu   
United States, Florida
Florida Cancer Specialists Recruiting
Sarasota, Florida, United States, 34232
Contact: Manish Patel    +001 (941) 377-9993    MPatel@flcancer.com   
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Mrinal Gounder    +001 (646) 497-9067    gounderm@mskcc.org   
United States, Tennessee
Tennessee Oncology, PLLC Recruiting
Nashville, Tennessee, United States, 37203
Contact: Todd Bauer    +001 (615) 329-7272    tbauer@tnonc.com   
Canada, Ontario
The Ottawa Hospital Recruiting
Ottawa, Ontario, Canada, K1H 8L6
Contact: Scott Laurie    613-737-7700 x70175    slaurie@toh.on.ca   
Japan
National Cancer Center Hospital Recruiting
Tokyo, Chuo-ku, Japan, 104-0045
Contact: Noboru Yamamoto    +81 3 35422511    nbryamam@ncc.go.jp   
Sponsors and Collaborators
Boehringer Ingelheim

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT03449381     History of Changes
Other Study ID Numbers: 1403-0001
2017-003210-95 ( EudraCT Number )
First Posted: February 28, 2018    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No