Efficacy and Safety of OncoGel™ Added to Chemotherapy and Radiation Before Surgery in Subjects With Esophageal Cancer

• Overall tumor response at the primary tumor site based on measurement of the longest diameter and largest cross-sectional area of the primary tumor (excluding involved lymph nodes) by spiral CT [ Time Frame: Screening and Week 12 ] [ Designated as safety issue: No ]
• Presence and viability of cancer in resection samples (eg, Pathologic complete response (pCR), Pathologic microscopic residual disease (pCRmicro), R0, R1, R2 resections [ Time Frame: After Week 12 and surgical resection ] [ Designated as safety issue: No ]
• Absence of metastatic disease at Week 12 (prior to surgery) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
• Ability to undergo surgical resection [ Time Frame: After Week 12 ] [ Designated as safety issue: No ]
• Adverse events including radiation and chemotherapy-related toxicities, and changes in clinical laboratory measurements [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
• Patient survival [ Time Frame: at least 1 year ] [ Designated as safety issue: No ]
• Change from baseline in dysphagia [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Change in quality of life [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Change in Karnofsky and/or ECOG performance status [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

• Overall tumor response at the primary tumor site based on measurement of the longest diameter and largest cross-sectional area of the primary tumor (excluding involved lymph nodes) by spiral CT. [ Time Frame: Screening and Week 12 ] [ Designated as safety issue: No ]
• Presence and viability of cancer in resection samples (eg, Pathologic complete response (pCR), Pathologic microscopic residual disease (pCRmicro), R0, R1, R2 resections). [ Time Frame: After Week 12 and surgical resection ] [ Designated as safety issue: No ]
• Absence of metastatic disease at Week 12 (prior to surgery) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
• Ability to undergo surgical resection [ Time Frame: After Week 12 ] [ Designated as safety issue: No ]
• Adverse events including radiation and chemotherapy-related toxicities, and changes in clinical laboratory measurements [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
• Patient survival [ Time Frame: at least 1 year ] [ Designated as safety issue: No ]
• Change from baseline in dysphagia [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Change in quality of life [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Change in Karnofsky and/or ECOG performance status [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

OncoGel is a new experimental drug delivery system that allows the slow continuous release of paclitaxel (an approved intravenous anticancer drug), from a gel (ReGel) over a long period of time. The gel will disappear in 4 to 6 weeks as it releases the paclitaxel.

The protocol is directed towards evaluating the efficacy and safety of paclitaxel delivered as a local, intralesional treatment when used in combination with chemotherapy (cisplatin and 5-FU) and radiation therapy before surgery.

The primary objective of this study is to evaluate the efficacy of OncoGel given in combination with standard chemotherapy (cisplatin and 5-FU) and radiation therapy in patients with previously untreated, resectable, local or local-regional adenosarcoma or squamous cell carcinoma.

All patients will receive IV cisplatin on Day 1 and Day 29 and IV 5-FU given continuously for 96 hours starting on Day 1 and Day 29. All patients will also receive out-patient radiation therapy for 28 treatments once per day for 5 1/2 weeks starting on Day 1.

Patients randomized to the OncoGel treatment group will have the OncoGel dose injected into their esophageal tumors during an endoscopic procedure just before starting systemic chemotherapy and radiation therapy.

All patients will have CT scans for tumor measurements before starting chemotherapy and 12 weeks later after completion of the radiation therapy and both cycles of chemotherapy.

During the chemotherapy and radiation therapy, physical exams, vital signs, routine blood tests will be performed. Patients will also be asked about their quality of life and ability to swallow.

In-patient surgery will be scheduled 4 to 6 weeks after completion of chemotherapy and radiation therapy. The resected esophagus and lymph nodes will be evaluated for the presence of residual tumor.

Patients will be followed at months 4, 5, 6, and then every 3 Months thereafter for survival and esophageal cancer status and treatment until the last patient enrolled has completed their Month 12 visit.

• Esophageal Cancer
• Adenocarcinoma of the Esophagus
• Squamous Cell Carcinoma

• Drug: OncoGel (Paclitaxel gel)
  6.3 mg/mL tumor volume, injected into the esophagus during endoscopy, once, before starting chemoradiotherapy
• Drug: cisplatin
  75 mg/m2 IV (in the vein) once on Day 1 and Day 29
• Drug: 5-FU
  1000 mg/m2/day, IV (in the vein) for 4 days (96 hours) for two cycles starting on Day 1 and Day 29
• Radiation: radiation therapy
  50.4 Gy, given in 28 treatments, once per day for 5 1/2 weeks
• Procedure: esophageal resection
  Removal of esophagus after completion of chemotherapy and radiation therapy

• Experimental: Group 1
  OncoGel, radiation therapy and systemic chemotherapy (cisplatin plus 5-FU) prior to surgical resection.
  Interventions:

  • Drug: OncoGel (Paclitaxel gel)
  • Drug: cisplatin
  • Drug: 5-FU
  • Radiation: radiation therapy
  • Procedure: esophageal resection
• Active Comparator: Group 2
  Radiation therapy and systemic chemotherapy (cisplatin plus 5-FU) prior to surgical resection.
  Interventions:

  • Drug: cisplatin
  • Drug: 5-FU
  • Radiation: radiation therapy
  • Procedure: esophageal resection

Inclusion Criteria:

1. Histologically or cytologically confirmed squamous cell carcinoma or adenocarcinoma of the esophagus. Stage T2-T3, N any, M0 (no evidence of disseminated cancer except regional involvement which may be designated as "M1a"). No evidence of metastatic disease
2. Medically able to tolerate major abdominal and/or thoracic surgery
3. Able to undergo EUS procedure and pass EUS probe through esophageal lumen
4. Able to receive concurrent systemic chemotherapy (cisplatin and 5-FU) and RT
5. Clinical management plan includes esophagectomy after completion of two courses of chemoradiation therapy
6. Karnofsky Performance Status of ≥ 60
7. Minimum life expectancy of 4 months

8. Hematologic function

   • Absolute neutrophil count (ANC) ≥ 1500/mm3
   • Platelet count ≥ 100,000/mm3
   • Hemoglobin ≥ 9 g/dL

9. Hepatic function:

   • Total bilirubin < 1.5 X upper limit of normal (ULN)
   • AST and ALT < 3 X ULN
   • Albumin ≥ 3.0 g/dL or ≥ 2.0 g/dL if the lower level is considered by the investigator to be due to nutritional depletion
10. Serum creatinine < 1.5 mg/dL and/or creatinine clearance ≥ 65 mL/min
11. ≥ 18 years old
12. If female, must be non-pregnant, nonlactating, of non-childbearing potential, or using adequate birth control
13. Capable of understanding and agreeing to fulfill the requirements of the protocol
14. Sign the IRB/EC approved consent form

Exclusion Criteria:

1. History of anaphylaxis to planned CT contrast agent
2. Prior esophageal stent insertion, laser, or photodynamic therapy
3. Prior chest RT or major esophageal surgery
4. Any prior receipt of cytotoxic chemotherapeutic agents
5. Prior receipt of other cancer treatments (ie, Chelation therapy), vaccines, or biological response modifiers/growth factors (ie, GM-CSF, IL-2) within the past 4 weeks.
6. Prior malignancy unless disease free for ≥ 3 years. Note: basal cell/squamous carcinoma of the skin, in situ cervical or breast carcinoma, or superficial transitional cell bladder carcinoma will be allowed. Subjects with a history of low risk prostatic carcinoma (ie, clinical stage 1 or 2a, Gleason score < or = 6 and PSA <10 ng/mL at diagnosis) will be allowed
7. Significant currently active systemic diseases including uncontrolled diabetes, severe heart disease (New York Heart Association Class III or IV), uncontrolled hypertension, myocardial infarction within 3 months, severe bronchial obstruction, uncontrolled seizure disorder, or peripheral neuropathy greater than CTCAE grade 1
8. Allergies to any of the active or inactive components of OncoGel (ie, allergies to degradable PLGA [poly(lactide-co-glycolide) sutures])
9. Receipt of an investigational drug or device within 30 days prior to signing informed consent
10. Any medical condition or other circumstance that, in the Investigator's opinion, would prevent completion of the study, interfere with analysis of the study results, or potentially adversely affect subject safety
11. Known esophageal varices