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A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 and 754111

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03964233
Recruitment Status : Recruiting
First Posted : May 28, 2019
Last Update Posted : September 9, 2020
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:

Phase Ia - Dose Escalation

The main objective of the dose-escalation part is to determine the maximum tolerated dose (MTD) of BI 907828 in combination with BI 754091 and BI 754111, based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 907828 in combination with BI 754091 and BI 754111, and to evaluate safety and tolerability of BI 907828 in combination with BI 754091 and BI 754111 by monitoring the occurrence and severity of adverse events (AEs).

The secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 907828, BI 754091 and BI 754111 based on Cmax and AUC0-tz, and the preliminary assessment of anti-tumor activity.

Phase Ib - Dose Expansion

The main objective of the dose-expansion part is to assess the preliminary efficacy of the combination of BI 907828, BI 754091, and BI 754111.

The secondary and further objectives are to further assess the safety, the PK profiles at the recommended dose for expansion (RDE), and to determine the Recommended Phase II Dose (RP2D).


Condition or disease Intervention/treatment Phase
Neoplasms Drug: BI 907828 Drug: BI 754091 Drug: BI 754111 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ia/Ib, Open Label, Dose-escalation Study of the Combination of BI 907828 With BI 754091 and BI 754111, Followed by Expansion Cohorts, in Patients With Advanced Solid Tumors
Actual Study Start Date : June 11, 2019
Estimated Primary Completion Date : September 9, 2022
Estimated Study Completion Date : May 15, 2024

Arm Intervention/treatment
Experimental: Dose Escalation - BI 907828 + BI 754091 + BI 754111
All neoplasms
Drug: BI 907828
Film-coated tablets

Drug: BI 754091
Solution for infusion

Drug: BI 754111
Solution for infusion

Experimental: Dose Expansion - Cohort 1-Arm A -BI 907828+BI 754091+BI 754111
NSCLC
Drug: BI 907828
Film-coated tablets

Drug: BI 754091
Solution for infusion

Drug: BI 754111
Solution for infusion

Experimental: Dose Expansion - Cohort 1 - Arm B - BI 754091 + BI 754111
NSCLC
Drug: BI 754091
Solution for infusion

Drug: BI 754111
Solution for infusion

Experimental: Dose Expansion - Cohort 1 - Arm C - BI 907828 + BI 754091
NSCLC
Drug: BI 907828
Film-coated tablets

Experimental: Dose Expansion - Cohort 2 - BI 907828 + BI 754091 + BI 754111
Melanoma
Drug: BI 907828
Film-coated tablets

Drug: BI 754091
Solution for infusion

Drug: BI 754111
Solution for infusion

Experimental: Dose Expansion - Cohort 3 - BI 907828 + BI 754091 + BI 754111
Liposarcoma
Drug: BI 907828
Film-coated tablets

Drug: BI 754091
Solution for infusion

Drug: BI 754111
Solution for infusion

Experimental: Dose Expansion - Cohort 4 - BI 907828 + BI 754091 + BI 754111
Hepatocellular carcinoma
Drug: BI 907828
Film-coated tablets

Drug: BI 754091
Solution for infusion

Drug: BI 754111
Solution for infusion




Primary Outcome Measures :
  1. Phase Ia - maximum tolerated dose (MTD) of BI 907828 in combination with BI 754091 and BI 754111 based on the number of patients with DLTs during the first treatment cycle [ Time Frame: Up to 35 Days ]
  2. Phase Ib - Objective response (OR) [ Time Frame: Up to 24 months ]

Secondary Outcome Measures :
  1. Phase Ia - Cmax : Maximum measured plasma concentration of BI 907828, BI 754091, and BI 754111 (during the first cycle) [ Time Frame: Up to 21 Days ]
  2. Phase Ia - AUC0-tz: Area under the concentration-time curve in plasma for BI 907828, BI 754091 and BI 754111 over the time interval from 0 to the last quantifiable time point (during the first cycle) [ Time Frame: Up to 21 Days ]
  3. Phase Ia - Number of patients with DLTs observed during the entire treatment period [ Time Frame: Up to 24 months ]
  4. Phase Ib - Objective Response (OR) [ Time Frame: Up to 24 months ]
  5. Phase Ib - Disease control (DC) [ Time Frame: Up to 24 months ]
  6. Phase Ib - Progression-Free Survival (PFS) [ Time Frame: Up to 24 months ]
  7. Phase Ib - In cohort 3 (liposarcoma and undifferentiated pleomorphic sarcoma): PFS rate at 12 and 24 weeks [ Time Frame: 12 and 24 weeks ]
  8. Phase Ib - Number of patients with DLTs [ Time Frame: Up to 2 years ]


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:

All cohorts:

  • Provision of signed and dated, written informed consent form ICF in accordance with International Council on Harmonization-Good Clinical Practice (ICH-GCP)and local legislation prior to any trial-specific procedures, sampling, or analyses.
  • Male or female ≥18 years old at the time of signature of the ICF.
  • ECOG performance status of 0 or 1.
  • Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement.
  • Patients with 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.
  • Previous treatment with an anti-PD-1/PD-L1 mAb is allowed as long as the last administration of the anti-PD-1/PD-L1 mAb on the previous treatment occurred a minimum of 28 days prior to the first administration of study treatment.
  • Patient must be willing to submit to the blood sampling for the Pharmacokinetics (PK), Pharmacodynamics (PD), biomarker, and PGx analyses.
  • Adequate organ function defined as all of the following (all screening labs should be performed locally within 10 days of treatment initiation):

    • Hematological

      • Absolute neutrophil count - ≥1.5 x 10^9/L
      • Platelets - ≥125 x 10^9/L
      • Hemoglobin 0 ≥9.0 g/dL or ≥5.6 mmol/L (red blood cell transfusion allowed to meet eligibility criteria)
    • Hepatic

      • Total bilirubin ≤ upper limit of normal (ULN), (patients with Gilbert's syndrome, total bilirubin must be < 2 x ULN)
      • Aspartate Transaminase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases
    • Renal

      --- Creatinine - ≤1.5 x ULN - Patients may enter if creatinine is >1.5 x ULN and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m^2 (assessed by Chronic Kidney Disease Epidemiology [CKDEPI] Collaboration equation); confirmation of eGFR is only required when creatinine is >1.5 X ULN

    • Coagulation --- International Normalised Ratio (INR) or Prothrombin Time (PT). Activated Partial Thromboplastin Time (aPTT) - ≤1.5 x institutional ULN. Patients taking low dose warfarin must have their INR followed closely and according to institutional guidelines
  • 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 medically acceptable 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.

Phase Ia (dose escalation part):

  • Patients with a confirmed diagnosis of unresectable, advanced and/or metastatic solid tumors (any type) irrespective of the TP53 mutation status,
  • Patient with either evaluable or non-evaluable disease.
  • Availability and willingness to provide a sample of archival Formalin-fixed paraffin embedded (FFPE) tumor tissue material

Phase Ib (expansion part):

  • At least one target lesion that can be accurately measured per RECIST 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least two weeks after any biopsy of the target lesion.
  • Expansion cohorts:

    • Cohort 1: Patients with unresectable, advanced and/or metastatic TP53 wt NSCLC, who received in the advanced/metastatic setting, at least one line of systemic medical treatment that includes, but is not limited to, a platinum-based combination chemotherapy and immune checkpoint inhibitor(s) except anti-LAG-3. Patients with NSCLC harboring genomic aberrations for which FDA approved targeted therapy is available such as non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS re-arrangement, and BRAF V600E mutation, must have received prior treatment with FDA-approved targeted therapy.
    • Cohort 2: Patients with unresectable, advanced and/or metastatic TP53 wt melanoma, who received in the advanced/metastatic setting, at least one line of systemic medical treatment that has included immune checkpoint inhibitor(s), except anti-LAG-3, and for patients with a V600 BRAF mutation, a prior treatment with BRAF and MEK inhibitors.
    • Cohort 3: Patients with unresectable, advanced and/or metastatic TP53 wt well-differentiated or dedifferentiated liposarcoma (n = 10 patients) or TP53 wt undifferentiated pleomorphic sarcoma (n = 10 patients), who received in the advanced/metastatic setting, at least one line of systemic medical treatment that may have included immune checkpoint inhibitor(s), except anti-LAG-3 antibody.
    • Cohort 4: Patients with unresectable, advanced and/or metastatic TP53 wt hepatocellular carcinoma (HCC), who received at least one line of systemic medical treatment in the advanced/metastatic setting, with or without prior treatment with anti-PD-1/PD-L1 antibody, and whose Child-Pugh score is 7 or less.

Exclusion criteria:

  • Previous administration of BI 907828 or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist, or anti-LAG-3 antibody.
  • In Phase Ib (expansion phase) only: a documented amino-acid altering mutation in TP53 occurring in the patient's tumor.
  • Active or untreated 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 closely and 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 4 weeks since receiving other investigational treatments. Patients who are in follow-up/observation for another clinical trial are eligible.
  • Patients who have been treated with any other anticancer drug within 4 weeks or within 5 half-life periods (whichever come earlier) prior to first administration of study treatment.
  • Persistent toxicity from previous treatments that has not resolved to ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 (except for alopecia and CTCAE Grade 2 neuropathy, or asthenia/fatigue).
  • Known history of human immunodeficiency virus (HIV) infection. Test results obtained in routine diagnostics are acceptable if done within 14 days before the informed consent date.
  • Any of the following laboratory evidence of hepatitis virus infection. Test results obtained in routine diagnostics are acceptable if done within 14 days before the informed consent date:

    • Positive results of hepatitis B surface (HBs) antigen
    • Presence of HBc antibody together with HBV-DNA
    • Presence of hepatitis C RNA However, in Phase Ib Cohort 4 (HCC), patients with HBV and/or HCV infection are allowed. Patients in Cohort 4 (HCC), with HBV infection must be receiving effective antiviral therapy (viral load <100 IU/mL).
  • Known hypersensitivity to the trial drugs or their 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.
  • History (including current) of interstitial lung disease or pneumonitis within the last 5 years.
  • History of severe hypersensitivity reactions to other monoclonal antibodies
  • Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of study treatment.
  • Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy
  • Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at start of treatment in this trial.
  • Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc) >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 factor that increases 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
    • Patients with an ejection fraction (EF) <50% or the lower limit of normal of the institutional standard will be excluded. 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 EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both.

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): NCT03964233


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 Cancer Center Recruiting
New Haven, Connecticut, United States, 06511
Contact: Navid Hafez    +001 (203) 785-7786    Navid.Hafez@yale.edu   
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, Texas
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78229
Contact: Anthony Tolcher    +001 (210) 580-9500    atolcher@nextoncology.com   
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: NCT03964233    
Other Study ID Numbers: 1403-0002
2019-001173-84 ( EudraCT Number )
First Posted: May 28, 2019    Key Record Dates
Last Update Posted: September 9, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https:// trials.boehringer-ingelheim.com/trial_results/ clinical_submission_documents.html to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement". Also, Researchers can use the following link http://trials.boehringer-ingelheim.

com/ to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website. The data shared are the raw clinical study data sets.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'.
URL: https://trials.boehringer-ingelheim.com

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