Phase 1/2a Study of DTA-H19 in Advanced Stage Ovarian Cancer

Phase 1/2a, Dose-Escalation, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Intraperitoneal Administration of DTA-H19 in Subjects With Advanced Stage Ovarian Cancer

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00826150

Enrollment

Registered

2009-01-21

Start date

2009-06-30

Completion date

2012-02-29

Last updated

2019-06-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ovarian Cancer

Keywords

ovarian cancer, H19 gene, plasmid, inodiftagene vixteplasmid

Brief summary

This study is designed to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of DTA-H19 administered intraperitoneally (IP) in subjects with advanced stage ovarian cancer, or primary peritoneal carcinoma

Detailed description

This is a Phase 1/2a, open label, dose escalation, repeat dose study in 11 subjects with recurrent, platinum resistant advanced stage ovarian cancer or primary peritoneal carcinoma designed to determine the tolerability, safety, quality of life, PK, and preliminary efficacy of DTA-H19 administered intraperitoneally(IP). Primary Objective: The primary objectives of this study are: * To determine the maximum tolerated dose (MTD) of IP DTA-H19; and, * To identify any dose limiting toxicities (DLTs). Secondary Objectives: Secondary objectives of this study are: * To determine quality of life of subjects with advanced ovarian cancer, primary peritoneal carcinoma treated with IP DTA-H19; * To determine the the reduction in malignant ascites as measured by Ultrasound and change in frequency of parecenteses necessary. * To determine the overall survival distribution.

Interventions

BIOLOGICALBC-819

Cohort #1: 60 mg IP weekly for 3 weeks, one week rest, then repeat for 2 more courses / 60 mg IP weekly for 3 weeks, four week rest, then repeat for 1 more course. Cohort #2: 120 mg IP weekly for 3 weeks, four week rest, then repeat for 1 more course. Cohort #3: 240 mg IP weekly for 3 weeks, four week rest, then repeat for 1 more course.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Provide written informed consent and be at least 18 years of age. * Have histopathologically documented epithelial ovarian carcinoma or primary peritoneal carcinoma with evidence of ascites. * Have either a) platinum-refractory disease (i.e. persistent disease following completion of platinum-based primary chemotherapy) and have failed at least primary platinum-based chemotherapy; or b) platinum-resistant recurrent disease and have failed at least one regimen of second line chemotherapy. * Be able to tolerate placement of IP catheter. * Be at least 2 weeks from last treatment to allow recovery from prior toxicity but in the judgment of the investigator with sufficient time to ensure that the effects of prior treatments will not confound safety evaluations. * Have a Karnofsky performance status score of ≥ 70%. * Not be of child-bearing potential. * Have a life expectancy of ≥ 3 months. * Have serum creatinine \< 2.0 mg/dL, total bilirubin less than the institution's 3x upper limit of normal (ULN); AST and ALT \<= 2.5 x ULN,total albumin ≥ 2.5 g/dL, PT, PTT, and PT/INR within normal limits, absolute neutrophil count (ANC) \> 1,500 x 103 cells/mL, platelets ≥ 100,000/mL, and hemoglobin ≥ 10 mg/dL. * Have a biopsy specimen or an ascites fluid that is positive for H19 expression. * Have screening procedures completed within 6-weeks before starting treatment. * No significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina or congestive heart failure. * \- No plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy for treatment of cancer while on this protocol.

Exclusion criteria

* Have evidence of extra abdominal disease with the exception of isolated small nodules (e.g., liver or pulmonary nodules) that are not causing symptoms. * Have known brain metastases. * Have known HIV infection. * Have known active viral or bacterial infections. * Have presence of any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol or follow up schedule. * Have a medical condition contraindicated for laparotomy, laparoscopy, or surgery. * Have significant bowel involvement denoted by persistent grade 3 vomiting (≥6 episodes in 24 hrs; IV fluids, or total parenteral nutrition (TPN) indicated ≥24 hrs) after removal of ascites, inability to tolerate oral diet or medications, requirement for total parenteral nutrition, or recent (past six weeks) episode of bowel obstruction. * Have a history of coagulopathy.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Dose-Limiting Toxicities	8 weeks	A dose limiting toxicity (DLT) was defined as any grade 3 or greater non-hematologic AE by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). If one subject in a cohort experienced a DLT, then three additional subjects had to be enrolled to that cohort unless a second subject in that cohort experiences a DLT. The next lower dose was to be considered the MTD.

Secondary

Measure	Time frame	Description
Solid Tumor Response	6 weeks	If measurable disease was present, then the response of each marker lesion was evaluated separately and rated for response according to RECIST criteria for solid tumors. Complete Response: Disappearance of the target lesion. Partial Response: At least a 30% decrease in the longest diameter of the target lesion. Stable Disease: No sufficient shrinkage to qualify for partial response, or sufficient increase to qualify for progressive disease. Progressive Disease: At least a 20% increase in the longest diameter of the target lesion.
Systemic BC-819 Pharmacokinetics (PK) by Treatment - T1/2 (Hours)	Before the start of the infusion of BC-819 and 2, 4, 6, 8, 24, and 48 hours after the start of the infusion	Blood was collected at the indicated time points, then analyzed with a quantitative polymerase chain reaction (Q-PCR) method to quantitate the amount of plasmid present.
Systemic BC-819 Pharmacokinetics (PK) - Maximum Observed Plasma Concentration (Cmax)	Before the start of the infusion of BC-819 and 2, 4, 6, 8, 24, and 48 hours after the start of the infusion	Blood was collected at the indicated time points, then analyzed with a quantitative polymerase chain reaction (Q-PCR) method to quantitate the amount of plasmid present.
Overall Survival in ITT Population	17.5 months	Overall survival, defined as the time from the start of treatment until the subject died, was estimated by Kaplan Meier curves.
Systemic BC-819 Pharmacokinetics (PK) by Treatment - AUClast	Before the start of the infusion of BC-819 and 2, 4, 6, 8, 24, and 48 hours after the start of the infusion	Blood was collected at the indicated time points, then analyzed with a quantitative polymerase chain reaction (Q-PCR) method to quantitate the amount of plasmid present.
Systemic BC-819 Pharmacokinetics (PK) by Treatment - AUCinf	Before the start of the infusion of BC-819 and 2, 4, 6, 8, 24, and 48 hours after the start of the infusion	Blood was collected at the indicated time points, then analyzed with a quantitative polymerase chain reaction (Q-PCR) method to quantitate the amount of plasmid present.
Overall Survival in PP	17.5 months	Overall survival, defined as the time from the start of treatment until the subject died, was estimated by Kaplan Meier curves.
Systemic BC-819 Pharmacokinetics (PK) by Treatment - Tmax (Hours)	Before the start of the infusion of BC-819 and 2, 4, 6, 8, 24, and 48 hours after the start of the infusion	Blood was collected at the indicated time points, then analyzed with a quantitative polymerase chain reaction (Q-PCR) method to quantitate the amount of plasmid present.

Countries

Israel

Participant flow

Recruitment details

Clinical sites

Participants by arm

Arm	Count
BC-819 60 mp IP 60 mg IP weekly for 3 weeks, one week rest, then repeat for 2 more courses / 60 mg IP weekly for 3 weeks, four week rest, then repeat for 1 more course.	8
BC-819 120 mg IP 120 mg IP weekly for 3 weeks, four week rest, then repeat for 1 more course.	3
BC-819 240 mg IP 240 mg IP weekly for 3 weeks, four week rest, then repeat for 1 more course.	3
Total	14

Baseline characteristics

Characteristic	BC-819 120 mg IP	BC-819 240 mg IP	BC-819 60 mp IP	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	3 Participants	3 Participants
Age, Categorical Between 18 and 65 years	3 Participants	3 Participants	5 Participants	11 Participants
Age, Continuous	61.3 years STANDARD_DEVIATION 3.1	54.3 years STANDARD_DEVIATION 7.6	60.9 years STANDARD_DEVIATION 12	59.6 years STANDARD_DEVIATION 9.8
Region of Enrollment Israel	3 participants	3 participants	8 participants	14 participants
Sex: Female, Male Female	3 Participants	3 Participants	8 Participants	14 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	3 / 8	0 / 3	0 / 3
other Total, other adverse events	8 / 8	3 / 3	3 / 3
serious Total, serious adverse events	6 / 8	1 / 3	0 / 3

Outcome results

Primary

Number of Participants With Dose-Limiting Toxicities

A dose limiting toxicity (DLT) was defined as any grade 3 or greater non-hematologic AE by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). If one subject in a cohort experienced a DLT, then three additional subjects had to be enrolled to that cohort unless a second subject in that cohort experiences a DLT. The next lower dose was to be considered the MTD.

Time frame: 8 weeks

Population: Per Protocol data set (PP): 11 subjects who met the study inclusion and exclusion criteria, received at least one course of treatment of the investigational product and had a follow-up disease assessment comprised the PP set (5 subjects from the 60 mg cohort, 3 subjects from the 120 mg cohort; 3 subjects from the 240 mg cohort).

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
BC-819 60 mg IP	Number of Participants With Dose-Limiting Toxicities	0 Participants
BC-819 120 mg IP	Number of Participants With Dose-Limiting Toxicities	0 Participants
BC-819 240 mg IP	Number of Participants With Dose-Limiting Toxicities	0 Participants

Secondary

Overall Survival in ITT Population

Overall survival, defined as the time from the start of treatment until the subject died, was estimated by Kaplan Meier curves.

Time frame: 17.5 months

Population: Intent to Treat (ITT) data set: subjects who participated in the study were included in the safety and in the ITT analysis. All 14 subjects who participated in the study were included in the ITT.

Arm	Measure	Value (MEDIAN)
BC-819 60 mg IP	Overall Survival in ITT Population	3.2 Months
BC-819 120 mg IP	Overall Survival in ITT Population	5.3 Months
BC-819 240 mg IP	Overall Survival in ITT Population	6.5 Months

Secondary

Overall Survival in PP

Overall survival, defined as the time from the start of treatment until the subject died, was estimated by Kaplan Meier curves.

Time frame: 17.5 months

Arm	Measure	Value (MEDIAN)
BC-819 60 mg IP	Overall Survival in PP	3.9 months
BC-819 120 mg IP	Overall Survival in PP	5.3 months
BC-819 240 mg IP	Overall Survival in PP	6.5 months

Secondary

Solid Tumor Response

If measurable disease was present, then the response of each marker lesion was evaluated separately and rated for response according to RECIST criteria for solid tumors. Complete Response: Disappearance of the target lesion. Partial Response: At least a 30% decrease in the longest diameter of the target lesion. Stable Disease: No sufficient shrinkage to qualify for partial response, or sufficient increase to qualify for progressive disease. Progressive Disease: At least a 20% increase in the longest diameter of the target lesion.

Time frame: 6 weeks

Population: Intent To Treat (ITT) data set: subjects who participated in the study were included in the safety and in the ITT analysis. All 14 subjects who participated in the study were included in the ITT. 13 patients of the ITT population (n=14) were evaluated (one patient was not assessed for solid tumor response in the BC-819 60 mg IP Arm).

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
BC-819 60 mg IP	Solid Tumor Response	Progressive Disease	2 Participants
BC-819 60 mg IP	Solid Tumor Response	Stable Disease	2 Participants
BC-819 60 mg IP	Solid Tumor Response	Not evaluable	3 Participants
BC-819 120 mg IP	Solid Tumor Response	Progressive Disease	1 Participants
BC-819 120 mg IP	Solid Tumor Response	Stable Disease	2 Participants
BC-819 120 mg IP	Solid Tumor Response	Not evaluable	0 Participants
BC-819 240 mg IP	Solid Tumor Response	Stable Disease	0 Participants
BC-819 240 mg IP	Solid Tumor Response	Not evaluable	0 Participants
BC-819 240 mg IP	Solid Tumor Response	Progressive Disease	3 Participants

Secondary

Systemic BC-819 Pharmacokinetics (PK) by Treatment - AUCinf

Blood was collected at the indicated time points, then analyzed with a quantitative polymerase chain reaction (Q-PCR) method to quantitate the amount of plasmid present.