A Study Combining LY2157299 With Temozolomide-based Radiochemotherapy in Patients With Newly Diagnosed Malignant Glioma

Phase 1b/2a Study Combining LY2157299 With Standard Temozolomide-based Radiochemotherapy in Patients With Newly Diagnosed Malignant Glioma

The purpose of this trial is to show proof of concept that by blocking the Transforming Growth Factor-beta signaling pathway in patients with Glioblastoma, there will be clinical benefit.

Phase 1b: To determine the safe and tolerable dose of LY2157299 in combination with radiochemotherapy with temozolomide for Phase 2 in patients with glioma eligible to receive radiochemotherapy with temozolomide (e.g. newly diagnosed malignant glioma World Health Organization Grade III and IV).

Phase 2a: To confirm the tolerability and evaluate the pharmacodynamic effect of LY2157299 in combination with standard radiochemotherapy in patients with newly diagnosed glioblastoma.

Study Overview

• Status: Completed
• Conditions: Glioma
• Intervention / Treatment: Drug: LY2157299; Drug: Radiation; Drug: Temozolomide

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Frankfurt, Germany, 60596
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Heidelberg, Germany, 69120
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Spain
  • Barcelona, Spain, 08035
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Madrid, Spain, 28041
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• United States
  • California
    • La Jolla, California, United States, 92093
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
    • San Francisco, California, United States, 94143
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Florida
    • Tampa, Florida, United States, 33612
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Illinois
    • Chicago, Illinois, United States, 60611
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with histologically proven, newly diagnosed and untreated intracranial glioblastoma including lower grade glioma which evolved into glioblastoma and who have not received any radiochemotherapy or who have World Health Organization Grade III malignant glioma (e.g., Anaplastic Astrocytomas, Anaplastic Oligoastrocytomas, Anaplastic Oligodendroglioma) (Phase 1b only) will be eligible for this protocol
• Biopsy or resection must have been performed no more than 6 weeks prior to treatment
• An Magnetic Resonance Imaging must be obtained within 72 hours after surgery, preferably within 48 hours
• Patient must not have had prior cranial radiation therapy
• Patients must not have received prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors Patients who received Gliadel wafers at the time of original resection will be excluded
• Patients must plan to begin partial brain radiotherapy within 2-6 weeks after surgery. Regular fractionated radiotherapy with photons (in any planning mode and possibly image-guided or stereotactic if deemed necessary) is performed according to the discretion of the investigator
• Patients must be willing to forego other cytotoxic and noncytotoxic drug therapy against the tumor while being treated with LY2157299 and temozolomide
• All patients must sign an informed consent indicating that they are aware of the investigational nature of this study
• Patients must have performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
• Patients must have adequate hematologic, hepatic and renal function
• Male and female patients with reproductive potential must use an approved contraceptive method,during and for 6 months after discontinuation of study treatment Women of childbearing potential must have a negative human chorionic gonadotropin pregnancy test documented within 14 days prior to treatment

Exclusion Criteria:

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or not approved use of a drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

• Have moderate or severe cardiac disease as defined by any of the following:

  • Have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension
  • Have documented major electrocardiogram (ECG) abnormalities that are symptomatic and are not medically controlled
  • Have major abnormalities documented by echocardiography with Doppler
  • Have predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress
• Are unable to swallow tablets or capsules
• Are pregnant or breastfeeding
• Have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
• Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and stopped all therapy for that disease for a minimum of 3 years are ineligible
• Have active infection that would interfere with the study objectives or influence the study compliance
• Stereotactic radiosurgery, such as Gamma-Knife treatment, and brachytherapy are not allowed in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: 160 mg LY2157299; During Radiation therapy: Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions. Approximate total dose = 60.0 Gy taken 5 days per week for 6 weeks.; LY2157299: 80 mg taken twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days.; Temozolomide: 75 mg/m2 taken daily for 6 weeks. After Radiation Therapy: LY2157299: 80 mg taken twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for a 6 cycles.; Temozolomide: 150 mg/m2 and then 200 mg/m2 daily during the off time of LY2157299. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.	Drug: LY2157299; Administered orally; Drug: Radiation; Administered as approved; Drug: Temozolomide; Administered orally
Experimental: Phase 1: 300 mg LY2157299; During Radiation therapy: Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions. Approximate total dose = 60.0 Gy taken 5 days per week for 6 weeks.; LY2157299: 150 mg taken twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days.; Temozolomide: 75 mg/m2 taken daily for 6 weeks. After Radiation Therapy: LY2157299: 150 mg taken twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for a 6 cycles.; Temozolomide: 150 mg/m2 and then 200 mg/m2 daily during the off time of LY2157299. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.	Drug: LY2157299; Administered orally; Drug: Radiation; Administered as approved; Drug: Temozolomide; Administered orally
Experimental: Phase 2: Established dose LY2157299; During Radiation therapy: Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions. Approximate total dose = 60.0 Gy taken 5 days per week for 6 weeks.; LY2157299: Phase 1 established dose taken twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days.; Temozolomide: 75 mg/m2 taken daily for 6 weeks. After Radiation Therapy: LY2157299: Phase 1 established dose taken twice daily for 14 days on followed 14 days of pause. This on/off schedule constitutes a cycle of 28 days. Taken for a 6 cycles.; Temozolomide: 150 mg/m2 and then 200 mg/m2 daily during the off time of LY2157299. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.	Drug: LY2157299; Administered orally; Drug: Radiation; Administered as approved; Drug: Temozolomide; Administered orally
Experimental: Phase 2: no LY2157299 (control); During Radiation therapy: Radiation:Approximate 1.8 - 2.0 Gy x 30 fractions. Approximate total dose = 60.0 Gy taken 5 days per week for 6 weeks.; Temozolomide: 75 mg/m2 taken daily for 6 weeks. After Radiation Therapy: Temozolomide: 150 mg/m2 and then 200 mg/m2 daily during the off time of LY2157299. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.	Drug: Radiation; Administered as approved; Drug: Temozolomide; Administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase 1: Recommended dose for Phase 2 portion	Baseline to phase 1 completion
Phase 2: Relationship of change in response biomarker to clinical benefit	Baseline through discontinuation from any cause

Secondary Outcome Measures

Outcome Measure	Time Frame
Phase 1: Pharmacokinetics - Concentration Maximum	Baseline, prior to first dose of cycle 1 and 2 and on days 1, 3, 8, 14, 15 and 16
Phase 1: Number of patients with a tumor response	Baseline to Progressive Disease
Phase 2: Overall Survival at 12 Months	Randomization to date of death from any cause at 12 months
Phase 2: Overall Survival	Randomization to date of death from any cause
Phase 2: Progression Free Survival	Randomization to measured progressive disease or death from any cause
Phase 2: Proportion of patients achieving an objective response (Response Rate)	Randomization to measured progressive disease
Phase 2: Duration of tumor Response	Time of response to measured progressive disease or death from any cause
Phase 2: Time to Treatment Failure	Randomization to the date of discontinuation of study treatment due to adverse event, progression of disease, or death from any cause
Phase 1: Pharmacokinetics - Time to Concentration Maximum	Baseline, prior to first dose of cycle 1 and 2 and on days 1, 3, 8, 14, 15 and 16
Phase 1: Pharmacokinetics - Area under the Curve	Days 12 to 14 in cycle 1 and in cycle 3
Phase 2: Change from baseline in MD Anderson Symptom Inventory - Brain Tumor	Baseline, 30 day post study day follow-up

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Wick A, Desjardins A, Suarez C, Forsyth P, Gueorguieva I, Burkholder T, Cleverly AL, Estrem ST, Wang S, Lahn MM, Guba SC, Capper D, Rodon J. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. Invest New Drugs. 2020 Oct;38(5):1570-1579. doi: 10.1007/s10637-020-00910-9. Epub 2020 Mar 5.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: October 12, 2010
• First Submitted That Met QC Criteria: October 12, 2010
• First Posted (Estimate): October 13, 2010

Study Record Updates

• Last Update Posted (Actual): February 16, 2017
• Last Update Submitted That Met QC Criteria: February 15, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Glioma; Glioblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: 11585; H9H-MC-JBAI (Other Identifier: Eli Lilly and Company)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No