Clinical trial NCT01119664: Combination Gene Transfer and Chemotherapy
Official title: A Pilot And Feasibility Trial Evaluating Two Different Chemotherapy Regimens In Combination With Intrapleural Adenoviral-Mediated Interferon-Alpha Gene Transfer For Malignant Pleural Mesothelioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Mesothelioma
Keywords: Adult subjects with malignant pleural mesothelioma who present for first (front) line or second line chemotherapy,
Lead sponsor: Abramson Cancer Center at Penn Medicine
Sponsor class: OTHER
First posted: 2010-05-07
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to find the safety of combination gene therapy and chemotherapy in patients with malignant pleural mesothelioma. Pleural catheter will be placed first, then pts will receive 2 doses of intrapleural vector followed by front line or second line chemotherapy 4-6 cycles every 21 days.

Detailed description: Malignant pleural mesothelioma (MPM) is a cancer for which there is no cure. The most effective combination chemotherapy, Pemetrexed (Alimta)/Cisplatin, has yielded overall response rates of up to 40%, but with improvements in overall median survival of only 3.5 months. Prior Phase I trials of intrapleural infusion (IP) of Ad.hIFN-beta (BG00001) were safe. The most recent trial of IP Ad.IFNalpha (SCH 721015) at a dose of 3e11 viral particles (vp) given three days apart was safe and well tolerated, and showed high levels of IFN in pleural fluid and serum. Our preclinical data modeling this proposed study suggest that two IP doses of Ad.IFN-alpha in combination with chemotherapy are well tolerated and markedly enhances efficacy. The purpose of the new study is to determine the safety of administrating intrapleural SCH 721015 (Ad.hIFN-alpha 2b) in combination with chemotherapy for the management of malignant pleural mesothelioma. This study will enroll subjects with pleural mesothelioma. Subjects will receive two fixed dosed of SCH 721015 followed by 4-6 cycles of chemotherapy. Subjects will require placement of a pleural catheter for administration of SCH 721015.

Some patients require a pleural catheter for control of pleural fluid while some will have it placed for research purpose only. Protocol participation is up to 15 years.

Eligibility criteria: Inclusion Criteria:

* -Pathologically documented malignant mesothelioma
* Must have evaluable disease by RECIST or Modified RECIST Criteria.
* ECOG Performance status equal to or lesser than 1.
* Must be at least 18 years of age.
* Women of childbearing potential and men must use acceptable contraceptive methods during treatment.
* Women of childbearing potential must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial.
* Must be able and willing to give written informed consent.
* No radiotherapy and/or treatment with chemotherapeutic, cytotoxic, or immunologic agents within 4 weeks prior to infusion of the IFN-alpha vector.
* Must have pleural tumor accessible for pleural catheter insertion. Patients with a previously inserted pleural catheter may enroll in the trial and can use the preexisting catheter for vector infusion as long as it is functional and has no evidence of local infection.
* FEV1 equal to or lesser than 1 liter or 40% of predicted value (post-pleural drainage).
* Acceptable hematologic value: granulocyte count equal to or lesser than 1,500/mm3, hemoglobin equal to or lesser than 9 g/dl, platelets equal to or lesser than 100,000/mm3
* Acceptable liver function: bilirubin equal to or less than 1.5 x the upper limit of normal; ALT, AST, and alkaline phosphatase equal to or less than 2.0 x the upper limit of normal
* Acceptable kidney function: creatinine less than 2.0 mg/dl (less than 1.5 mg/dl required for Cisplatin administration) or Creatinine clearance greater than 50.
* Acceptable coagulation status: PT equal to or less than 1.5 x normal, PTT less than 1.5 x normal. However, patients on stable, chronic anti-coagulation therapy with therapeutic anti-coagulation levels will be allowed to enroll in the study.
* Serum albumin must be greater than 2.5 g/dl
* Must have an anti-adenoviral neutralizing antibody titer equal to or less than 1:1000. This will be measured by sub-investigators in the Thoracic Oncology Research Laboratory under standardized (but not GCP) conditions. Results must be known before performing any other research procedures.
* Must have medical insurance coverage (or other means of payment) providing for standard medical interventions in clinical trial, including combination chemotherapy.

Exclusion Criteria:

* Presence of significant pericardial effusion on baseline CT scan of the chest.
* Documented immunodeficiency such as HIV infection.
* Evidence of chronic active Hepatitis B (positive for HBsAg). Prior HBV exposure without evidence of chronic active Hepatitis B is not exclusionary.
* Use of concurrent systemic steroids (greater than10 mg of prednisone per day), immunosuppressives, or any other medications that can directly or indirectly suppress the immune system.
* Presence of any other life-threatening illness, such as unstable angina, severe oxygen dependence, significant chronic obstructive pulmonary disease (COPD), end stage liver or renal disease.
* Rapidly re-accumulating,symptomatic malignant pleural effusion status-post thoracentesis or pleural catheter insertion that requires immediate mechanical or chemical pleurodesis for adequate palliation.
* Presence of untreated brain metastases. Subjects with a prior history of brain metastases will have a CT or MRI scan of the brain to rule out activity.
* Prior bone marrow or stem cell transplants -Female patients who are actively nursing are excluded.
* Patients who have undergone any prior major surgery (excluding pleural catheter placement or infusaport insertion) less than 2 weeks prior to study enrollment.
* Lack of medical insurance coverage (or other form of payment) for standard medical interventions, particularly combination chemotherapy.

Primary outcomes:
measure: To determine the safety of administering intrapleural SCH 721015, Ad.hIFN-alpha2b (Adenoviral-mediated Interferon-alpha) in combination with chemotherapy for the management of MPM.
timeFrame: On going throughout the conduct of the trial
Secondary outcomes:
measure: To estimate objective response rates and distribution
timeFrame: On going throughout the conduct of the trial
measure: Time to Progression
timeFrame: On going throughout the conduct of the trial
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Andrew Haas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sterman DH, Alley E, Stevenson JP, Friedberg J, Metzger S, Recio A, Moon EK, Haas AR, Vachani A, Katz SI, Sun J, Heitjan DF, Hwang WT, Litzky L, Yearley JH, Tan KS, Papasavvas E, Kennedy P, Montaner LJ, Cengel KA, Simone CB 2nd, Culligan M, Langer CJ, Albelda SM. Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNalpha Combined with Chemotherapy. Clin Cancer Res. 2016 Aug 1;22(15):3791-800. doi: 10.1158/1078-0432.CCR-15-2133. Epub 2016 Mar 11.