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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.

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ClinicalTrials.gov Identifier: NCT03099174
Recruitment Status : Recruiting
First Posted : April 4, 2017
Last Update Posted : March 6, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE March 31, 2017
First Posted Date  ICMJE April 4, 2017
Last Update Posted Date March 6, 2019
Actual Study Start Date  ICMJE May 4, 2017
Estimated Primary Completion Date April 10, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 4, 2019)
  • Cohorts A, B,C & D - Maximum Tolerated Dose (MTD) [ Time Frame: 28 days ]
  • Cohorts A, B,C & D - Number of patients with dose limiting toxicities (DLT) in the Maximum Tolerated Dose (MTD) evaluation period [ Time Frame: 28 days ]
  • Cohorts E & F: objective response (OR), defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. [ Time Frame: 12 months ]
  • Cohorts D1 & D2 - Progression-free survival (PFS) rate [ Time Frame: 18 Months ]
Original Primary Outcome Measures  ICMJE
 (submitted: March 31, 2017)
  • Cohorts A, B,C & D - Maximum Tolerated Dose (MTD) [ Time Frame: 28 days ]
  • Cohorts A, B,C & D - Number of patients with dose limiting toxicities (DLT) in the Maximum Tolerated Dose (MTD) evaluation period [ Time Frame: 28 days ]
  • Cohorts E & F: objective response (OR), defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. [ Time Frame: 12 months ]
Change History Complete list of historical versions of study NCT03099174 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 4, 2019)
  • Cohorts E, F, D1 & D2: 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 ]
  • Cohorts E, F, D1 & D2: 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 ]
  • Cohorts E, F, D1 & D2: 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 ]
  • Cohorts E, F, D1 & D2: 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 ]
  • Cohorts E, F, D1 & D2: Progression-free survival (PFS) [ Time Frame: 12 months ]
  • Cohorts D1 & D2: Objective response (OR) defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 [ Time Frame: 12 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2017)
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE An Open Label, Phase Ib, Dose-escalation Study Evaluating the Safety and Tolerability of Xentuzumab and Abemaciclib in Patients With Locally Advanced or Metastatic Solid Tumours and in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-positive, HER2-, Breast Cancer, Followed by Expansion Cohorts.
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Neoplasms
  • Breast Neoplasms
Intervention  ICMJE
  • Drug: Xentuzumab
    Once weekly administrated through one hour intravenous infusion
  • Drug: Abemaciclib
    Treatment/28-day cycle p.o. Q12H on Days 1-28 (Starting dose Cohort A) Abbreviations: PO = orally; Q12H = every 12 (± 2) hours
  • Drug: Letrozole
    once a day
  • Drug: Anastrozole
    once a day
  • Drug: Fulvestrant
    once a month, with an additional dose given two weeks after the first dose. Each dose is given as two slow injections lasting one to two minutes, with one injection being given into the muscle of each buttock
Study Arms
  • Experimental: Cohort A
    Xentuzumab + Abemaciclib (Dose 1)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
  • Experimental: Cohort B
    Xentuzumab + Abemaciclib + Letrozole (Dose 2)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
    • Drug: Letrozole
  • Experimental: Cohort C
    Xentuzumab + Abemaciclib + Anastrozole (Dose 3)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
    • Drug: Anastrozole
  • Experimental: Cohort D
    Xentuzumab + Abemaciclib + Fulvestrant (Dose 4)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
    • Drug: Fulvestrant
  • Experimental: Cohort E
    Xentuzumab + Abemaciclib (Dose 1)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
  • Experimental: Cohort F
    Xentuzumab + Abemaciclib + Fulvestrant (Dose 4)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
    • Drug: Fulvestrant
  • Experimental: Cohort D1
    Xentuzumab + Abemaciclib + Fulvestrant (Dose 4)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
    • Drug: Fulvestrant
  • Experimental: Cohort D2
    Xentuzumab + Abemaciclib + Fulvestrant (Dose 4)
    Interventions:
    • Drug: Xentuzumab
    • Drug: Abemaciclib
    • Drug: Fulvestrant
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: December 21, 2018)
148
Original Estimated Enrollment  ICMJE
 (submitted: March 31, 2017)
90
Estimated Study Completion Date November 8, 2021
Estimated Primary Completion Date April 10, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 3 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 due to surgical/natural menopause requires at least one of the following conditions:

      • prior bilateral oophorectomy
      • age ≥ 60 years
      • age < 60 years and amenorrheic (in the absence of tamoxifen,toremifene, ovarian suppression, or chemotherapy) for at least 12 months; and follicle-stimulating 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.
  • Further inclusion criteria apply

Exclusion Criteria:

Cohorts A, B, C, D (dose finding), E and F:

  • 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 treatment 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 anti-cancer chemotherapy, biological or radiation therapy, androgens, thalidomide, other anticancer agents, or any investigational drug within 21 days (14 days for nonmyelosuppressive agents); and/or 4 weeks 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 treatment related toxicity from previous therapy of > CTCAE grade 1 at study entry (except for stable sensory neuropathy ≤ CTCAE grade 2 and alopecia)
  • 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, completed radiotherapy for at least 4 weeks or are on 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 (defined by HgBA1C > 8%)
  • 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 or fungal infection (that is, requiring IV antibiotics or therapy at time of initiating study treatment), 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.
  • Further exclusion criteria apply
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE
Contact: Boehringer Ingelheim Call Center 1-800-243-0127 clintriage.rdg@boehringer-ingelheim.com
Listed Location Countries  ICMJE France,   Japan,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03099174
Other Study ID Numbers  ICMJE 1280.18
2016-003142-85 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement 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 March 2019

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