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A Phase 1B/2 Study of LY2940680 in Combination With Weekly Paclitaxel, Carboplatin, and Radiation in Localized Adenocarcinoma of the Esophagus or Gastroesophageal Junction

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2015 by M.D. Anderson Cancer Center
Sponsor:
Collaborators:
Eli Lilly and Company
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT02530437
First received: August 19, 2015
Last updated: NA
Last verified: August 2015
History: No changes posted
  Purpose

The goal of Phase 1B of this clinical research study is to find a dose of LY2940680 that can be given safely with the chemotherapy drugs carboplatin and paclitaxel and radiotherapy to patients with esophageal or gastroesophageal junction cancer.

The goal of Phase 2 of this clinical research study is to learn if LY2940680 given with chemoradiation can help to control the disease. The safety of this treatment combination will continue to be studied.


Condition Intervention Phase
Esophageal Cancer
Drug: LY2940680
Drug: Paclitaxel
Drug: Carboplatin
Radiation: Radiation Therapy
Procedure: Endoscopy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1B/2 Study of LY2940680 in Combination With Weekly Paclitaxel, Carboplatin, and Radiation in Localized Adenocarcinoma of the Esophagus or Gastroesophageal Junction

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Toxicity of LY2940680 with Paclitaxel, Carboplatin and Radiation Therapy [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
    Initially, if </= 1/6 patients develop dose-limiting toxicities (DLTs) (DLT period is from the start of LY2940680 to 5 weeks after the completion of biochemoradiation) that are deemed to be associated with LY2940680, then current dose/schedule combination of LY2940680 (i.e., 400 mg/day for 38 days) is considered safe and will be used in phase II part of the study. Otherwise, if more than 1 DLT occurs in the first 6 patients, an additional cohort of 6 patients will receive LY2940680 at 200 mg every day for 38 days. If this dose/schedule combination is established to be safe (i.e., with </= 1/6 DLTs), then this dose/schedule combination will be used in phase II part.

  • Pathologic Complete Response (pathCR) [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Primary endpoint for the phase II part of the study is the pathologic complete response (pathCR) rate and a pathCR rate of at least 35% (>/= 40% is desirable) will be of interest.


Secondary Outcome Measures:
  • Biomarker Expression Levels [ Time Frame: Baseline and before surgery ] [ Designated as safety issue: No ]
    For both the phase IB and phase II parts of the study, tissue samples collected and biomarker expression levels assessed at baseline and at the time of surgery. A linear mixed effect model will be fit to assess the change of biomarkers over time, which takes into consideration of the association among multiple marker observations from the same patient. Outcome variable is biomarker expression level and the covariates include time, treatment step and time by treatment interaction. Biomarker expression may be log-transformed prior to fit the model in order to satisfy the normality assumption. Biomarkers include expression of Shh, Ih, Gli1, and Gli2, Patch 2 and sFRP1 mRNA using real-time qPCR as well as refined and expand the pathway-associated markers using gene expression signatures.


Estimated Enrollment: 66
Study Start Date: November 2015
Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase IB: LY2940680 + Chemoradiation
Phase 1B: Participants take LY2940680 1 time a day by mouth. Radiation therapy delivered every weekday for 5 ½ weeks. Once a week during this time, participants also receive Paclitaxel and Carboplatin by vein.
Drug: LY2940680

Phase IB: 400 mg by mouth daily for 38 days, starting on first chemoradiation day.

Phase II: Step 1 - (First 27 participants): As determined in Phase Ib mg (fixed dose) by mouth daily for 7 days followed by LY2940680 plus chemoradiation.

Phase II: Step 2 - (Second set of 27 participants): As determined in Phase Ib mg (fixed dose) by mouth daily for 38 days, starting on first chemoradiation day.

Drug: Paclitaxel
50 mg/m2/week by vein on first radiation day of each week for 5 doses.
Other Name: Taxol
Drug: Carboplatin
AUC 2mg/ml/min by vein on first radiation day of each week for 5 doses.
Other Name: Paraplatin
Radiation: Radiation Therapy
1.8 Gy per weekday for 5 1/2 weeks.
Other Names:
  • XRT
  • External beam radiation therapy
Experimental: LY2940680 Before Chemoradiation

Phase II: If participant is one of the first 27 enrolled in Phase 2, they will take LY2940680 for 7 days before beginning chemoradiation. Participant continues to take LY2940680 every day until they complete chemoradiation. Radiation therapy delivered every weekday for 5 ½ weeks. Once a week during this time, participants also receive Paclitaxel and Carboplatin by vein.

Research upper endoscopy on day 8 from the start of treatment.

Drug: LY2940680

Phase IB: 400 mg by mouth daily for 38 days, starting on first chemoradiation day.

Phase II: Step 1 - (First 27 participants): As determined in Phase Ib mg (fixed dose) by mouth daily for 7 days followed by LY2940680 plus chemoradiation.

Phase II: Step 2 - (Second set of 27 participants): As determined in Phase Ib mg (fixed dose) by mouth daily for 38 days, starting on first chemoradiation day.

Drug: Paclitaxel
50 mg/m2/week by vein on first radiation day of each week for 5 doses.
Other Name: Taxol
Drug: Carboplatin
AUC 2mg/ml/min by vein on first radiation day of each week for 5 doses.
Other Name: Paraplatin
Radiation: Radiation Therapy
1.8 Gy per weekday for 5 1/2 weeks.
Other Names:
  • XRT
  • External beam radiation therapy
Procedure: Endoscopy
Upper endoscopy performed on day 8 to obtain pictures of the tumor for comparison with the baseline and to obtain tumor tissue for biomarker assessment.
Experimental: LY2940680 + Chemoradiation

Phase II: If participant joins the study after 27 participants have been enrolled, they will start LY2940680 on the same day they begin chemoradiation. Participant will continue to take LY2940680 every day until they complete chemoradiation. Radiation therapy delivered every weekday for 5 ½ weeks. Once a week during this time, participants also receive Paclitaxel and Carboplatin by vein.

Research upper endoscopy on day 8 from the start of treatment.

Drug: LY2940680

Phase IB: 400 mg by mouth daily for 38 days, starting on first chemoradiation day.

Phase II: Step 1 - (First 27 participants): As determined in Phase Ib mg (fixed dose) by mouth daily for 7 days followed by LY2940680 plus chemoradiation.

Phase II: Step 2 - (Second set of 27 participants): As determined in Phase Ib mg (fixed dose) by mouth daily for 38 days, starting on first chemoradiation day.

Drug: Paclitaxel
50 mg/m2/week by vein on first radiation day of each week for 5 doses.
Other Name: Taxol
Drug: Carboplatin
AUC 2mg/ml/min by vein on first radiation day of each week for 5 doses.
Other Name: Paraplatin
Radiation: Radiation Therapy
1.8 Gy per weekday for 5 1/2 weeks.
Other Names:
  • XRT
  • External beam radiation therapy
Procedure: Endoscopy
Upper endoscopy performed on day 8 to obtain pictures of the tumor for comparison with the baseline and to obtain tumor tissue for biomarker assessment.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction (EAC).
  2. Male or female patients whose age is greater than or equal to 18 years (Because nonclinical studies suggest that LY2940680 may adversely affect the development and maintenance of teeth, bones, and growth plates in a pediatric population, children are excluded from this study. In addition, EAC is extremely rare in children).
  3. Localized EAC and its baseline clinical stage determined as: T2-T3N0 or T1-3N+. Imaging studies suspicious for metastases must be followed with a negative biopsy before a patient can enter the study.
  4. Patients with malignant celiac nodes are eligible if the primary lesion is in the mid-thoracic or distal thoracic esophagus or it is involving the gastroesophageal junction.
  5. Tumor must have labeling index of greater than or equal to 5% of the nuclear Gli-1 (integral biomarker performed in the MD Anderson Cancer Center CLIA laboratory) for patient to be eligible in this trial (if enough archival tissue is not available to determine labeling index, patient must agree to a biopsy to be eligible for the study).
  6. Tumor may not extend greater than 4 cm below the gastroesophageal junction.
  7. ECOG performance status 0 or 1.
  8. Able to swallow capsules.
  9. All patients must be willing to provide research tumor tissue for biomarker studies at baseline (from archival tumor tissue or through endoscopy if sufficient archival tissue is not available). All patients must also allow biomarker studies on the tissue obtained through surgery to remove the primary cancer.
  10. Phase II only: Patients volunteering for the Phase II part of the protocol must be willing to undergo a research endoscopy for tissue collection on day 8 (+/- 2 days) from the beginning of therapy.
  11. Absolute neutrophil count greater than or equal to 1500/mm^3; Platelets greater than or equal to 100,000/mm^3; Hemoglobin greater than or equal to 8 g/dL; Serum creatinine less than or equal to 2 x Upper Limit of Normal (ULN); ALT and AST less than or equal to 2.5 x ULN; Serum bilirubin less than or equal to 1.5 x ULN.
  12. Patient must be able to comprehend the approved consent document and have the willingness to sign it. The patient prior to enrollment and the administration of any protocol-specific therapy must sign the consent document.
  13. Willingness and ability to comply with study procedures and follow-up examinations.
  14. Must be considered medically fit for operation as determined by multidisciplinary evaluation.
  15. Effects of LY2940680 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because Hh signal pathway inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, males and females with reproductive potential must agree to use two forms of medically approved contraceptive precautions and for at least 6 months following the last dose of biochemoradiation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  16. (# 15 continued) Women of childbearing potential are defined as follows: Having regular menstrual cycles; Has amenorrhea, irregular menstrual cycles or using a contraceptive method that precludes withdrawal bleeding; Have had a tubal ligation. Women are considered not to be of childbearing potential for the following reasons: Had hysterectomy and/or bilateral oophorectomy; Post-menopausal defined by amenorrhea for at least 1 year in a woman >45 years old.
  17. Females with childbearing potential must have a negative serum pregnancy test within 14 days prior to treatment start.

Exclusion Criteria:

  1. Baseline clinical stage of T1N0 or inoperable T4 (unequivocal organ involvement) are to be excluded.
  2. Unequivocal metastatic tumor at baseline.
  3. Tracheo-esophageal (TE) fistula or direct invasion into the tracheo-bronchial mucosa. A bronchoscopy (biopsy and cytology should be performed) is required to exclude TE fistula or tracheo-bronchial involvement in patients with a tumor located at <26 cm from the incisors.
  4. Cervical esophageal cancer will not be entered in this study.
  5. Any prior chemotherapy, surgery, or radiotherapy for EAC.
  6. Prior mediastinal irradiation (for any reason).
  7. Clinically significant ulcerative colitis, inflammatory bowel disease, or partial or complete small bowel obstruction are to be excluded.
  8. Malabsorption syndrome or other condition that would interfere with intestinal absorption are excluded.
  9. Pregnant or nursing females are to be excluded. Pregnant women are excluded from this study because LY2940680 is a Hh pathway-inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY2940680, breastfeeding should be discontinued if the mother is treated with LY2940680. These potential risks may also apply to other agents used in this study.
  10. Presence of other significant cancer(s) or history of other significant cancer(s) within the last 3 years (patients who have been cancer-free for 3 years, or have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma of the cervix are eligible).
  11. Known viral or other chronic types hepatitides or cirrhosis.
  12. Uncontrolled concurrent illness including, but not limited to: serious uncontrolled infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia that interfere with blood pressure, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with the study requirements.
  13. Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation.
  14. Patients who are receiving concurrent non-protocol anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy, or tumor embolization) are to be excluded.
  15. Patients may not be receiving any other investigational agents.
  16. Patients with known hypersensitivity to taxanes or platinums are to be excluded.
  17. Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible. Patients on strong CYP3A inhibitors will also be excluded.
  18. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LY2940680. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  19. Any other conditions or circumstances that would, in the opinion of the Investigator, make the patient unsuitable for participation in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02530437

Contacts
Contact: Jaffer Ajani, MD 713-792-2828

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Eli Lilly and Company
Investigators
Principal Investigator: Jaffer Ajani, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02530437     History of Changes
Other Study ID Numbers: 2014-0966, CA172741
Study First Received: August 19, 2015
Last Updated: August 19, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
LY2940680
Esophageal Cancer
Adenocarcinoma of the Esophagus
Adenocarcinoma of the Gastroesophageal Junction
Chemoradiation
Paclitaxel (Protein-Bound)
Taxol
Carboplatin
Paraplatin
Radiation therapy
XRT
External beam
Endoscopy

Additional relevant MeSH terms:
Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Digestive System Diseases
Digestive System Neoplasms
Esophageal Diseases
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Head and Neck Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Carboplatin
Paclitaxel
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Tubulin Modulators

ClinicalTrials.gov processed this record on September 01, 2015