Taladegib, Paclitaxel, Carboplatin, and Radiation Therapy in Treating Patients With Localized Esophageal or Gastroesophageal Junction Cancer

PRIMARY OBJECTIVES:

I. To evaluate the toxicity of taladegib administered orally daily concurrently with weekly paclitaxel, carboplatin and radiation therapy in patients with localized nuclear glioma-associated oncogene homolog (Gli-1) expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase IB) II. To assess the rate of pathologic complete response (pathCR) when taladegib is administered orally daily concurrently with weekly paclitaxel, carboplatin, and radiation therapy in patients with localized nuclear Gli-1 expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of biochemoradiation in the phase II study. II. To assess additional biomarkers (hedgehog \[Hh\] related and Hh unrelated) in sequentially procured tissues (biopsies and resected specimens).

III. Assess if taladegib down modulates its target (Gli-1) in the first cohort (where taladegib will be administered alone for the first 7 days) of the phase II study.

IV. Assess relapse-free survival and overall survival.

OUTLINE:

PHASE IB: Patients receive taladegib orally (PO) once daily (QD) on days 1-38, paclitaxel intravenously (IV) over 3 hours on the first radiation day of each week for 5 doses, carboplatin IV over 2 hours on the first radiation day of each week for 5 doses, and undergo external beam radiation therapy 5 days weekly on 28 consecutive weekdays for 5.5 weeks.

PHASE II: Patients are assigned to 1 of 2 steps.

STEP I: Patients receive taladegib PO for 7 days, followed by taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB.

STEP II: Patients receive taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB.

After completion of study treatment, patients are followed up at 3 months, every 3-6 months for 1 year, every 6 months for 2 years, and at years 4 and 5.

• Carboplatin (Drug), also known as Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo: Given IV
• External Beam Radiation Therapy (Radiation), also known as Definitive Radiation Therapy, EBRT, External Beam Radiation, External Beam Radiotherapy, External Beam RT, external radiation, External Radiation Therapy, external-beam radiation, Radiation, External Beam: Undergo external beam radiation therapy
• Laboratory Biomarker Analysis (Other): Correlative studies
• Paclitaxel (Drug), also known as Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat: Given IV
• Taladegib (Drug), also known as Benzamide, 4-Fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)-1-phthalazinyl)-4-piperidinyl)-2-(trifluoromethyl)-, LY-2940680, LY2940680: Given PO

Primary outcomes

• Safety of Taladegib When Given in Combination With Paclitaxel, Carboplatin, and Radiation Therapy Defined by Dose-limiting Toxicities (Phase IB) [Up to 5 weeks]: The safety data will be summarized using frequencies and percentages by adverse event category, grade and attributions.
• Pathologic Complete Response Rate (Phase II) [Up to 4 years and 10 months]: A pathologic complete response (pathCR) rate of at least 35% (>= 40% is desirable) will be of interest. The pathCR rate in each of the treatment step will be estimated, along with the 95% confidence interval.

Secondary outcomes

• Change in Biomarker Expression Levels of Primary and Secondary Resistance [Baseline to the time of surgery]: A linear mixed effect model will be used to assess the change of biomarkers over time. The outcome variable will be biomarker expression level and the covariates will include time, treatment step and time by treatment interaction. The biomarker expression may be log-transformed prior to fit the model in order to satisfy the normality assumption. Also, a logistic regression model will be used for the binary outcome of pathCR, using treatment step, baseline biomarker and the change of biomarker between baseline and at surgery as covariates.
• Relapse-free Survival [Up to 4 years and 10 months]: Kaplan-Meier method will be used to estimate the probabilities of relapse-free survival.
• Overall Survival [Up to 4 years and 10 months]: Kaplan-Meier method will be used to estimate the probabilities of overall survival.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction (EAC)
* Localized EAC and its baseline clinical stage determined as: T2-T3N0 or T1-3N positive (+); imaging studies suspicious for metastases must be followed with a negative biopsy before a patient can enter the study
* 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
* Tumor must have labeling index of >= 5% of the nuclear Gli-1 (integral biomarker) performed in the MD Anderson Cancer Center Clinical Laboratory Improvement Amendment (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)
* Tumor may not extend > 4 cm below the gastroesophageal junction
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* 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
* 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
* Absolute neutrophil count >= 1500/mm\^3
* Platelets greater >= 100,000/mm\^3
* Hemoglobin >= 8 g/dL
* Serum creatinine =< 2 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
* Serum bilirubin =< 1.5 x ULN
* 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
* Willingness and ability to comply with study procedures and follow-up examinations
* Must be considered medically fit for operation as determined by multidisciplinary evaluation
* Males and females with reproductive potential must agree to use 2 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
* 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
* Females with childbearing potential must have a negative serum pregnancy test within 14 days prior to treatment start

Exclusion Criteria:

* Baseline clinical stage of T1N0 or inoperable T4 (unequivocal organ involvement) are to be excluded
* Unequivocal metastatic tumor at baseline
* 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
* Cervical esophageal cancer will not be entered in this study
* Any prior chemotherapy, surgery, or radiotherapy for EAC
* Prior mediastinal irradiation (for any reason)
* Clinically significant ulcerative colitis, inflammatory bowel disease, or partial or complete small bowel obstruction are to be excluded
* Malabsorption syndrome or other condition that would interfere with intestinal absorption are excluded
* Pregnant or nursing females are to be excluded; breastfeeding should be discontinued if the mother is treated with taladegib
* 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)
* Known active viral or other chronic types hepatitides (hepatitis B, C) or cirrhosis
* 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
* Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation
* 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
* Patients may not be receiving any other investigational agents
* Patients with known hypersensitivity to taxanes or platinums are to be excluded
* Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin) are ineligible; patients on strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors will also be excluded
* Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
* Any other conditions or circumstances that would, in the opinion of the investigator, make the patient unsuitable for participation in the study

Participant flow

Outcome results

• Safety of Taladegib When Given in Combination With Paclitaxel, Carboplatin, and Radiation Therapy Defined by Dose-limiting Toxicities (Phase IB) (Primary)
• Pathologic Complete Response Rate (Phase II) (Primary), Count of participants, Participants: Phase 1 B 4
• Change in Biomarker Expression Levels of Primary and Secondary Resistance (Secondary)
• Relapse-free Survival (Secondary), Median, months: Phase 1 B 14 (2 to 28)
• Overall Survival (Secondary), Median, months: Phase 1 B 27 (20 to 49)

Adverse events

Time frame: Baseline to up to 4 years and 10 months

Serious adverse events by term

Other adverse events by term

27 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2017-06-27)

• Jaffer A Ajani, Principal investigator, M.D. Anderson Cancer Center