A Phase I/II Study of Oblimersen Plus Cisplatin and Fluorouracil in Gastric & Esophageal Junction Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00064259
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 80.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Drugs used in chemotherapy such as cisplatin and fluorouracil use different ways to stop tumor cells from dividing so they stop growing or die. Oblimersen may increase the effectiveness of chemotherapy by making tumor cells more sensitive to the drugs. This phase I/II trial is studying the side effects and best dose of oblimersen when given with cisplatin and fluorouracil and to see how well they work in treating patients with locally advanced, recurrent, or metastatic cancer of the esophagus, gastroesophageal junction, or stomach.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Squamous Cell Carcinoma of the Esophagus; Stage III Esophageal Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer	Biological: oblimersen sodium; Drug: cisplatin; Drug: fluorouracil	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. The escalation portion of the study will determine the MTD of G3139/Cisplatin and will help determine the toxicities of this combination.

2. Once the MTD is determined, an additional 12 patients will be enrolled in order to obtain a set of tumor biopsies for microarray analysis.

SECONDARY OBJECTIVES:

1. The collection of additional toxicity data for this combination

OUTLINE: This is a pilot, multicenter, dose-escalation study of oblimersen.

Phase I: Patients receive oblimersen IV continuously on days 1-7, fluorouracil IV continuously on days 4-8, and cisplatin IV on day 4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of oblimersen until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 12 patients are treated at the MTD.

Phase II: Patients receive treatment as in phase I with oblimersen at the MTD.

PROJECTED ACCRUAL: Approximately 37-97 patients (3-36 for phase I and 34-67 for phase II) will be accrued for this study within 15-18 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Oblimersen in Combination With Cisplatin and Fluorouracil in Patients With Advanced Esophageal, Gastro-Esophageal Junction and Gastric Cancer
• Study Start Date: Jun 1, 2003
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (oblimersen sodium) Phase I: Patients receive oblimersen IV continuously on days 1-7, fluorouracil IV continuously on days 4-8, and cisplatin IV on day 4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of oblimersen until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 12 patients are treated at the MTD. Phase II: Patients receive treatment as in phase I with oblimersen at the MTD.

Biological: oblimersen sodium; Given IV; Other Names: augmerosen G3139 G3139 bcl-2 antisense oligodeoxynucleotide Genasense ; Drug: cisplatin; Given IV; Other Names: CACP CDDP CPDD DDP ; Drug: fluorouracil; Given IV; Other Names: 5-fluorouracil 5-Fluracil 5-FU

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Oblimersen in Combination With Cisplatin and 5-FU [21 days]

   Adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria (version 2.0). DLT was defined as grade 3 to 4 hematologic toxicity lasting more than 1 week after 5-FU/cisplatin, grade 3 to 4 nausea or vomiting occurring later than 11 days after cisplatin, grade 3 to 4 diarrhea occurring later than 10 days after 5-FU, and grade 3 to 4 mucositis at the beginning of the next cycle.

Secondary Outcome Measures

1. Microarray Data [Up to 12 weeks]

   This will be primarily descriptive, and will seek to compare patterns of gene expression pre- and post-treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the esophagus, gastro- esophageal junction, or stomach; patients with squamous cell carcinoma of the esophagus will also be eligible, patients must have locally advanced, recurrent or metastatic disease, not amenable to complete surgical resection or definitive radiation therapy

• Measurable and/or evaluable disease

• May have had prior surgery, radiation therapy, combined modality chemo- radiation, or at most one prior chemotherapy regimen for advanced, recurrent or metastatic disease;

• Life expectancy of greater than 12 weeks

• ECOG performance status =<2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,500/uL

• Platelets >= 100,000/uL

• Total bilirubin within normal institutional limits

• Creatinine =< 1.5 OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• Ability to understand and the willingness to sign a written informed consent document

• Patients with accessible tumors are obliged to participate in biopsies 1 and 2; accessible tumors are defined as tumors reachable by EGD, or metastases, which, in the opinion of the treating physician can be biopsied with commonly utilized biopsy methods (such as CT guided biopsy); biopsy #3 on day 6 is optional; patients who do not have have accessible tumor tissue may participate in the study if at least one tumor deposit is measurable

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 21 days (6 weeks for nitrosoureas or mitomycin C, two weeks if prior treatment was a weekly regimen) prior to entering the study or those who have not recovered from adverse events (grade 2 or worse) due to agents administered earlier

• Patients who have had photodynamic therapy within 4 weeks of proposed study entry will be excluded; patients will be allowed to receive concurrent photodynamic therapy for obstruction untreatable by stent, laser, or dilation; patients who do require concurrent photodynamic therapy and who are participating in the serial biopsy portion of the study must wait until after cycle 1 and its biopsies are completed

• Patients may not be receiving any other investigational agents

• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to anti- sense oligonucleotides, cisplatin, fluorouracil or other agents used in the study

• Patients may not have received G3139 previously

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study because G3139 is an anti- sense oligonucleotide 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 G3139, breastfeeding should be discontinued if the mother is treated with G3139; these potential risks may also apply to other agents used in this study

• Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with G3139 or other agents administered during the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Montefiore Medical Center	Bronx	New York	United States	10467-2490

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andreas Kaubisch, Montefiore Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00064259
• Other Study ID Numbers: NCI-2012-03134; 02-66; N01CM62204
• First Posted: Jul 9, 2003
• Last Update Posted: Feb 17, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Adenocarcinoma; Stomach Neoplasms; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Recurrence; Fluorouracil; Oblimersen

Study Results

Participant Flow

Arm/Group Title	Oblimersen 3 mg/kg/d +Cisplatin 100 mg/m2 +5-FU 1000 mg/m2	Oblimersen 3 mg/kg/d +Cisplatin 75 mg/m2 +5-FU 750 mg/m2	Oblimersen 5 mg/kg/d +Cisplatin 75 mg/m2 +5-FU 750 mg/m2	Oblimersen 7 mg/kg/d +Cisplatin 75 mg/m2 +5-FU 750 mg/m2
Arm/Group Description	Patients received oblimersen as a continuous intravenous infusion (CIVI) on days 1 to 7 at 3 mg/kg/d in combination with CIVI 5-FU 1000 mg/m2/d on days 4 to 7 and cisplatin 100 mg/m2 on day 4.	Patients received oblimersen as a continuous intravenous infusion (CIVI) on days 1 to 7 at 3 mg/kg/d in combination with CIVI 5-FU 750 mg/m2/d on days 4 to 7 and cisplatin 75 mg/m2 on day 4.	Patients received oblimersen as a continuous intravenous infusion (CIVI) on days 1 to 7 at 5 mg/kg/d in combination with CIVI 5-FU 750 mg/m2/d on days 4 to 7 and cisplatin 75 mg/m2 on day 4.	Patients received oblimersen as a continuous intravenous infusion (CIVI) on days 1 to 7 at 7 mg/kg/d in combination with CIVI 5-FU 750 mg/m2/d on days 4 to 7 and cisplatin 75 mg/m2 on day 4.
Period Title: Overall Study
STARTED	4	4	6	1
COMPLETED	3	4	6	0
NOT COMPLETED	1	0	0	1

Baseline Characteristics

Arm/Group Title	Oblimersen + Cisplatin + 5-FU
Arm/Group Description	Oblimersen dose levels (3, 5, or 7 mg/kg/d) on days 1 to 7 in combination with 5-FU (1000 mg/m2/d or 750 mg/m2/d) on days 4 to 7 and Cisplatin (100 mg/m2 or 75 mg/m2) on day 4.
Overall Participants	15
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55.0
Sex: Female, Male (Count of Participants)
Female	6 40%
Male	9 60%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Oblimersen in Combination With Cisplatin and 5-FU
Description	Adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria (version 2.0). DLT was defined as grade 3 to 4 hematologic toxicity lasting more than 1 week after 5-FU/cisplatin, grade 3 to 4 nausea or vomiting occurring later than 11 days after cisplatin, grade 3 to 4 diarrhea occurring later than 10 days after 5-FU, and grade 3 to 4 mucositis at the beginning of the next cycle.
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oblimersen + Cisplatin + 5-FU
Arm/Group Description	Oblimersen dose levels (3, 5, or 7 mg/kg/d) on days 1 to 7 in combination with 5-FU (1000 mg/m2/d or 750 mg/m2/d) on days 4 to 7 and Cisplatin (100 mg/m2 or 75 mg/m2) on day 4.
Measure Participants	15
Number [mg/kg/d]	5

2. Secondary Outcome

Title	Microarray Data
Description	This will be primarily descriptive, and will seek to compare patterns of gene expression pre- and post-treatment.
Time Frame	Up to 12 weeks

Outcome Measure Data

Analysis Population Description

Outcome was not analysed. No patients had samples obtained for microarray analysis.

Arm/Group Title	Treatment (Oblimersen Sodium)
Arm/Group Description	Phase I: Patients receive oblimersen IV continuously on days 1-7, fluorouracil IV continuously on days 4-8, and cisplatin IV on day 4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of oblimersen until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 12 patients are treated at the MTD. Phase II: Patients receive treatment as in phase I with oblimersen at the MTD. oblimersen sodium: Given IV cisplatin: Given IV fluorouracil: Given IV
Measure Participants	0

Adverse Events

Arm/Group Title	Oblimersen + Cisplatin + 5-FU
Arm/Group Description	Oblimersen dose levels (3, 5, or 7 mg/kg/d) on days 1 to 7 in combination with 5-FU (1000 mg/m2/d or 750 mg/m2/d) on days 4 to 7 and Cisplatin (100 mg/m2 or 75 mg/m2) on day 4.
All Cause Mortality
	Oblimersen + Cisplatin + 5-FU
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Oblimersen + Cisplatin + 5-FU
	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)
Blood and lymphatic system disorders
Neutropenia	5/15 (33.3%)
Anemia	1/15 (6.7%)
Thrombocytopenia	1/15 (6.7%)
Gastrointestinal disorders
Vomiting	1/15 (6.7%)
Dysphagia	1/15 (6.7%)
General disorders
Fatigue	2/15 (13.3%)
Dizziness	2/15 (13.3%)
Pleural effusion	1/15 (6.7%)
Ascites	1/15 (6.7%)
Hepatobiliary disorders
Transaminase elevation	1/15 (6.7%)
Alkaline phosphatase	1/15 (6.7%)
Infections and infestations
Infection	3/15 (20%)
Metabolism and nutrition disorders
Hypokalemia	4/15 (26.7%)
Hyponatremia	1/15 (6.7%)
Dehydration	2/15 (13.3%)
Nervous system disorders
Sensory neuropathy	1/15 (6.7%)
Motor neuropathy	1/15 (6.7%)
Renal and urinary disorders
Creatinine	1/15 (6.7%)
Ureteral obstruction	1/15 (6.7%)
Vascular disorders
Vascular/Thrombosis	2/15 (13.3%)
Other (Not Including Serious) Adverse Events
	Oblimersen + Cisplatin + 5-FU
	Affected / at Risk (%)	# Events
Total	9/15 (60%)
Blood and lymphatic system disorders
Neutropenia	3/15 (20%)
Anemia	8/15 (53.3%)
Thrombocytopenia	2/15 (13.3%)
Gastrointestinal disorders
Mucositis	4/15 (26.7%)
Nausea	4/15 (26.7%)
Vomiting	2/15 (13.3%)
Diarrhea	2/15 (13.3%)
General disorders
Weight loss	2/15 (13.3%)
Fatigue	3/15 (20%)
Dizziness	1/15 (6.7%)
Peripheral edema	2/15 (13.3%)
Hepatobiliary disorders
Alkaline phosphatase	2/15 (13.3%)
Metabolism and nutrition disorders
Anorexia	1/15 (6.7%)
Hyperglycemia	1/15 (6.7%)
Hypomagnesaemia	1/15 (6.7%)
Dehydration	1/15 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.