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This Study in Patients With Different Types of Cancer (Solid Tumours) Aims to Find a Safe Dose of Xentuzumab in Combination With Abemaciclib With or Without Hormonal Therapies. The Study Also Tests How Effective These Medicines Are in Patients With Lung and Breast Cancer.

NCT03099174

Description:

For each dose finding cohorts (A, B, C and D): The primary objective of each dose finding cohort is to determine the maximum tolerated dose (MTD) / recommended phase II dose (RP2D) of xentuzumab in combination with abemaciclib with or without hormonal therapy (letrozole, anastrozole, fulvestrant). Dose limiting toxicities (DLT) will be assessed during the first treatment cycle to assess the MTD/RP2D. In case that no MTD is reached a RP2D dose will be determined taking into account safety data and other available information. This will be agreed with the Steering Committee. For each expansion cohorts (E, F, D1 and D2): The objectives of the expansion cohorts are to assess the anti-tumour activity of xentuzumab in combination with abemaciclib in patients with non-small cell lung cancer (cohort E). Tentatively a cohort F may be opened to assess the anti-tumour activity of the triplet combination xentuzumab / abemaciclib and fulvestrant in a single-arm expansion group of patients with locally advanced / metastatic hormone receptor positive (HR+) breast cancer who have progressed following prior aromatase inhibitor therapy and prior CDK4/6 inhibitor treatment. Cohort F will only be opened if indicated by emerging data from ongoing clinical trials. The primary objective of cohorts D1 and D2 is to assess the anti-tumour activity of the triplet combination xentuzumab, abemaciclib and fulvestrant in patients with locally advanced / metastatic HR+ breast cancer who have progressed on prior endocrine therapy. Cohort D1 will assess the anti-tumour activity for subjects with visceral metastasis and Cohort D2 for subjects with non-visceral metastasis.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: This Study in Patients With Different Types of Cancer (Solid Tumours) Aims to Find a Safe Dose of Xentuzumab in Combination With Abemaciclib With or Without Hormonal Therapies. The Study Also Tests How Effective These Medicines Are in Patients With Lung and Breast Cancer.
  • Official Title: An Open Label, Phase Ib Dose-escalation Study Evaluating the Safety and Tolerability of BI 836845 and Abemaciclib in Patients With Locally Advanced or Metastatic Solid Tumors and in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-positive Breast Cancer, Followed by Expansion Cohorts

Clinical Trial IDs

  • ORG STUDY ID: 1280.18
  • NCT ID: NCT03099174

Conditions

  • Neoplasms
  • Breast Neoplasms

Interventions

DrugSynonymsArms
XentuzumabCohort A
AbemaciclibCohort A
LetrozoleCohort B
AnastrozoleCohort C
FulvestrantCohort D

Purpose

For each dose finding cohorts (A, B, C and D): The primary objective of each dose finding cohort is to determine the maximum tolerated dose (MTD) / recommended phase II dose (RP2D) of xentuzumab in combination with abemaciclib with or without hormonal therapy (letrozole, anastrozole, fulvestrant). Dose limiting toxicities (DLT) will be assessed during the first treatment cycle to assess the MTD/RP2D. In case that no MTD is reached a RP2D dose will be determined taking into account safety data and other available information. This will be agreed with the Steering Committee. For each expansion cohorts (E and F): The objectives of the expansion cohorts are to assess the anti-tumour activity of xentuzumab in combination with abemaciclib in patients with non-small cell lung cancer (cohort E). Tentatively a cohort F may be opened to assess the anti-tumour activity of the triplet combination xentuzumab / abemaciclib and fulvestrant in a single-arm expansion group of patients with locally advanced / metastatic hormone receptor positive (HR+) breast cancer who have progressed following prior aromatase inhibitor therapy and prior CDK4/6 inhibitor treatment. Cohort F will only be opened if indicated by emerging data from ongoing clinical trials.

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalXentuzumab + Abemaciclib (Dose 1)
  • Xentuzumab
  • Abemaciclib
Cohort BExperimentalXentuzumab + Abemaciclib + Letrozole (Dose 2)
  • Xentuzumab
  • Abemaciclib
  • Letrozole
Cohort CExperimentalXentuzumab + Abemaciclib + Anastrozole (Dose 3)
  • Xentuzumab
  • Abemaciclib
  • Anastrozole
Cohort DExperimentalXentuzumab + Abemaciclib + Fulvestrant (Dose 4)
  • Xentuzumab
  • Abemaciclib
  • Fulvestrant
Cohort EExperimentalXentuzumab + Abemaciclib (Dose 1)
  • Xentuzumab
  • Abemaciclib
Cohort FExperimentalXentuzumab + Abemaciclib + Fulvestrant (Dose 4)
  • Xentuzumab
  • Abemaciclib
  • Fulvestrant

Eligibility Criteria

        Inclusion criteria:

        Cohort A (Solid Tumours)

          -  Age >= 18 years (>=20 years for Japan only) at screening

          -  Signed and dated written informed consent in accordance with GCP (Good Clinical
             Practice and local legislation prior to admission to the trial

          -  WHO/ECOG (World Health Organization / Eastern Cooperative Oncology Group) performance
             status 0-1 assessed at screening

          -  Patient must be able to swallow oral capsules.

          -  Male or female patients ready and able to use highly effective methods of birth
             control during the study and for 12 weeks following the last dose of abemaciclib per
             ICH (International Conference on Harmonization) 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.
             Women of childbearing potential must have a negative serum pregnancy test at
             screening.

          -  Patients with histologically or cytologically confirmed diagnosis of advanced and/or
             metastatic, measurable or evaluable, non-resectable solid tumours

          -  Patients must have received and failed, or have been intolerant to, all treatment
             known to confer clinical benefit or have no therapeutic options available as deemed
             appropriate by their treating physician

          -  Life expectancy >= 3 months in the opinion of the investigator assessed at screening;

        Cohorts B, C, D, F (Breast Cancer):

          -  Age >= 18 years (>=20 years for Japan only) at screening

          -  Signed and dated written informed consent in accordance with GCP and local legislation
             prior to admission to the trial

          -  WHO/ECOG performance status 0-1 assessed at screening

          -  Patient must be able to swallow oral capsules.

          -  Women who have postmenopausal status due to either surgical/natural menopause or
             chemical ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1)
             with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or
             radiation-induced ovarian suppression

               -  postmenopausal status defined as meeting one of the following conditions:

                    -  prior bilateral oophorectomy

                    -  age >= 60 years

                    -  age < 60 years and amenorrheic (non-treatment-induced amenorrhea secondary
                       to tamoxifen, toremifene, ovarian suppression, or chemotherapy) for at least
                       12 months; and folliclestimulating hormone (FSH) and estradiol within the
                       postmenopausal range as per institutional reference ranges.

               -  Postmenopausal status due to radiation-induced ovarian suppression must be
                  confirmed by FSH and estradiol level in the postmenopausal range

          -  Histologically or cytologically proven diagnosis of breast cancer with evidence of
             locally advanced or metastatic disease not amenable to resection or radiation

          -  HR+ (local lab results at screening or, if not available, at the time of diagnosis) To
             fulfil the requirement of HR+ disease, the primary tumour or metastatic lesion of the
             breast cancer must express at least one of the hormone receptors (estrogen receptor
             [ER] or progesterone receptor [PgR]) by immunohistochemistry (IHC). Estrogen receptor
             and PgR assays are considered positive if there are at least 1% positive tumour nuclei
             in the sample as defined in the relevant American Society of Clinical Oncology
             (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).

          -  HER2 negative (local lab results at screening or, if not available, at the time of
             diagnosis) as defined by the most recent American Society of Clinical Oncology
             (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).

          -  Previous adjuvant and neoadjuvant chemotherapy is permitted. 0-2 prior lines of
             chemotherapy for the metastatic setting are allowed.

          -  At least 1 lesion (measurable or non-measurable) that can be accurately assessed at
             baseline with CT or MRI or PET-CT (CT portion of diagnostic quality) and which is
             suitable for accurate repeated measurement. For Cohort F only: patients should have at
             least one measurable lesion.

          -  Cohort B, C, D, F Must be eligible for the corresponding hormonal therapy (letrozole,
             anastrozole or fulvestrant). For Cohorts B and C previous treatment with fulvestrant
             or exemestane is allowed. For Cohort D and F prior therapy with non steroidal
             aromatase inhibitors (anastrozole, letrozole) or exemestane are permitted

          -  Cohort F only: Postmenopausal with locally advanced or metastatic HR+ breast cancer
             and refractory to aromatase inhibitors therapy and CDK4/6 inhibitor treatment (e.g.,
             palbociclib or ribociclib) for locally advanced or metastatic breast cancer.Resistance
             to aromatase inhibitors therapy is defined as the following:

               -  disease recurrence while on, or within 12 months of end of adjuvant treatment
                  with letrozole, anastrozole, or exemestane;

               -  or disease progression while on, or within one month of end of letrozole,
                  anastrozole, or exemestane.

        Cohort E (NSCLC (Non-Small Cell Lung Cancer)):

          -  Age >= 18 years (>=20 years for Japan only) at screening

          -  Signed and dated written informed consent in accordance with GCP and local legislation
             prior to admission to the trial

          -  WHO/ECOG performance status 0-1 assessed at screening

          -  Patient must be able to swallow oral capsules.

          -  Male or female patients ready and able to use highly effective methods of birth
             control during the study and for 12 weeks following the last dose of abemaciclib 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. Women of childbearing potential must have a
             negative serum pregnancy test at screening.

          -  Histologically or cytologically confirmed diagnosis of stage IV NSCLC.

          -  The participant must have progressed after platinum-based chemotherapy AND
             immunotherapy (unless deemed inappropriate candidates for immunotherapy by their
             treating physician) AND have received a maximum of 2 other prior chemotherapy for
             advanced and/or metastatic disease OR must be judged by the physician as ineligible
             for further standard second-line chemotherapy. Prior treatment with epidermal growth
             factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and anaplastic lymphoma kinase
             (ALK) inhibitors is mandatory in participants whose tumour has EGFR-activating
             mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant
             therapies are permitted.

          -  Have adequate organ function including haematology, renal, and liver.

          -  Have measureable disease per Response Evaluation Criteria In Solid Tumours (RECIST)
             1.1.

        Exclusion criteria:

        All cohorts:

          -  Any documented active or suspected malignancy or history of malignancy, other than the
             disease under study, within 3 years prior to screening, except appropriately treated
             basal cell carcinoma of the skin or in situ carcinoma of uterine cervix or ductal
             carcinoma in situ (DCIS) if properly treated in opinion of the investigator.

          -  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

          -  Previous enrolment in this trial

          -  Currently enrolled in another investigational device or drug study, or less than 21
             days since ending another investigational device or drug study(s), or receiving other
             investigational treatment(s).

          -  Chronic alcohol or drug abuse or any condition that, in the investigator's opinion,
             makes them an unreliable study subject or unlikely to complete the trial

          -  Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
             Men who plan to father a child while in the trial.

          -  Prior chemotherapy, biological or radiation therapy, androgens, thalidomide, other
             anticancer agents, or any investigational drug or corticosteroids within 21 days;
             and/or three half-lives for immunotherapy, before starting any of the trial drugs.

          -  Prior anti CDK (Cyclin-dependent Kinase) agents (except cohort F)

          -  Prior radiotherapy to >= 25% of bone marrow regardless of when it was received

          -  Unresolved toxicity from prior therapy > Common Terminology Criteria for Adverse
             Events (CTCAE) grade 1

          -  Previous treatment with IGF (Insulin-like Growth Factor)-1R targeting compounds

          -  Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or
             leptomeningeal disease, as indicated by clinical symptoms, cerebral oedema, and/or
             progressive growth. History of CNS metastases or cord compression are eligible if they
             have been definitively treated (e.g. radiotherapy, stereotactic surgery) and are
             clinically stable, off anticonvulsants and steroids for at least 4 weeks. Patients
             with brain metastases are eligible if they are asymptomatic or treated at a stable
             dose of steroids for at least 4 weeks. Patients are not eligible if they have spinal
             cord compression.

          -  Any evidence of severe or uncontrolled systemic disease as judged by the Investigator.

          -  Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following: ANC < 1.5 x 109/L, platelets < 100 x 109/L, haemoglobin <90g/L, ALT > 2.5 x
             ULN or > 5 x ULN in the presence of liver metastases, total bilirubin >1.5 x ULN or >3
             x ULN in patients with Gilbert's Syndrome, serum creatinine > 1.5 x ULN concurrent
             with creatinine clearance <= 50 mL/min.

          -  Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi
             Syndrome or renal tubular acidosis

          -  Refractory nausea and vomiting, chronic GI diseases, inability to swallow the product,
             or previous significant bowel resection that would preclude adequate absorption of
             abemaciclib or resulting in baseline Grade 2 or higher diarrhoea.

          -  History of hypersensitivity to active or inactive excipients of xentuzumab,
             abemaciclib or letrozole/anastrozole/fulvestrant, or loperamide hydrochloride, or
             drugs with similar chemical structures

          -  Patients with Diabetes Type I or uncontrolled Type II

          -  Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of
             life threatening complications in the short term including patients with massive
             uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and
             over 50% of liver involvement in metastases.

          -  Prior hematopoietic stem cell or bone marrow transplant

          -  Have a personal history of any of the following conditions: syncope of either
             unexplained or cardiovascular etiology, ventricular arrhythmia (including but not
             limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac
             arrest. Subjects with controlled atrial fibrillation for >30 days prior to study
             treatment are eligible.

          -  Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. The
             primary prophylactic use of G-CSF is not permitted but it may be used to treat
             treatment emergent neutropenia.

          -  Have had major surgery (excluding biopsy) < 28 days of the initial dose of any of the
             study drugs or planned major surgery during study participation.

          -  Have active bacterial, fungal, and/or known viral infection (for example, human
             immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen, or hepatitis C
             antibodies). Screening is not required for enrolment.

          -  Patients with baseline Grade >=2 hyperglycaemia or patients with baseline Grade >= 2
             Diarrhoea

          -  Patients needing treatment with CYP3A4 inhibitors/inducers cannot be included in the
             trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohorts A, B,C & D - Maximum Tolerated Dose (MTD)
Time Frame:28 days
Safety Issue:
Description:Cohorts A, B,C & D - Maximum Tolerated Dose (MTD)

Secondary Outcome Measures

Measure:Cohorts E and F: Disease control (DC) defined as best overall response of complete response (CR) or partial response (PR) or confirmed stable disease (SD) where best overall response is defined according to RECIST version 1.1
Time Frame:12 months
Safety Issue:
Description:Cohorts E and F: Disease control (DC) defined as best overall response of complete response (CR) or partial response (PR) or confirmed stable disease (SD) where best overall response is defined according to RECIST version 1.1
Measure:Cohorts E & F: Time to objective response defined as the time from first treatment administration until first documented complete response (CR) or partial response (PR).
Time Frame:up to 12 months
Safety Issue:
Description:Cohorts E & F: Time to objective response defined as the time from first treatment administration until first documented complete response (CR) or partial response (PR).
Measure:Cohorts E & F - Duration of objective response defined as the time from first documented complete response (CR) or partial response (PR) until the earliest of disease progression or death among patients with objective response
Time Frame:up to 12 months
Safety Issue:
Description:Cohorts E & F - Duration of objective response defined as the time from first documented complete response (CR) or partial response (PR) until the earliest of disease progression or death among patients with objective response
Measure:Cohorts E & F - Duration of disease control is defined as the time from first treatment administration until the earliest of disease progression or death, among patients with disease control
Time Frame:12 months
Safety Issue:
Description:Cohorts E & F - Duration of disease control is defined as the time from first treatment administration until the earliest of disease progression or death, among patients with disease control
Measure:Cohorts E & F - Progression-free survival (PFS) defined as the time from first treatment administration until tumour progression according to Response Evaluation Criteria In Solid Tumours (RECIST 1.1) or death from any cause, whichever occurs earlier
Time Frame:12 months
Safety Issue:
Description:Cohorts E & F - Progression-free survival (PFS) defined as the time from first treatment administration until tumour progression according to Response Evaluation Criteria In Solid Tumours (RECIST 1.1) or death from any cause, whichever occurs earlier

Details

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

Last Updated

September 5, 2017