Clinical trial NCT02910882: PEGPH20 Plus Gemcitabine With Radiotherapy in Patients With Localized, Unresectable Pancreatic Cancer
Official title: A Phase II Study Combining PEGPH20 With Concurrent Gemcitabine and Radiotherapy in Patients With Localized, Unresectable Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma Non-resectable
Keywords: Pancreas Cancer
Unresectable
Chemoradiation
PEGPH20
Lead sponsor: Scripps Health
Sponsor class: OTHER
First posted: 2016-09-22
Enrollment: 4
Sex: ALL
Maximum age (years): 90
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single arm phase II trial assessing the potential activity of combination PEGPH20 plus Gemcitabine with radiotherapy in ten patients with localized, unresectable pancreatic adenocarcinoma.

Detailed description: This is a pilot trial evaluating the safety and potential efficacy of PEGylated Recombinant Human Hyaluronidase (PEGPH20) plus concurrent Gemcitabine and radiotherapy. Recognizing that PEGPH20 has not been previously delivered with radiotherapy but is unlikely to contribute to increased toxicities, this trial will have an abbreviated sequential dose escalation schema for the first three patients. PEGPH20 will be given twice per week for the first 28 days and then weekly for another 2 weeks during radiotherapy. Gemcitabine will be delivered weekly at the first day of radiotherapy and continued weekly, per published literature. Patients will remain on study for three months. The duration of active treatment with PEGPH20 and Gemcitabine plus radiotherapy will continue for 5-6 weeks. Efficacy outcome will occur 6-8 weeks after the completion of radiotherapy.

Eligibility criteria: Inclusion Criteria:

Subjects must satisfy all the following inclusion criteria to be enrolled in the study:

1. Signed, written Institutional Review Board/Ethics Committee-approved Informed Consent Form;
2. For men and women of reproductive potential, agreement to use an effective contraceptive method from the time of screening and throughout their time on study. Effective contraceptive methods consist of prior sterilization, intra-uterine device, oral or injectable contraceptives, and/or barrier methods. Abstinence alone is not considered an adequate contraceptive measure for the purposes of this study;
3. Patients with previously untreated localized, unresectable histologically confirmed pancreatic adenocarcinoma (unresectable will be defined as locally advanced disease or when patients cannot have or refuse surgery);
4. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L;
5. Platelets ≥ 100 x 109/L;
6. Hgb ≥ 9 g/dL;
7. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x \[Upper Limit of Normal (ULN)\];
8. Bilirubin ≤ 1.5 x ULN;
9. GFR ≥ 30 mL/min;
10. Patient has no clinically significant abnormalities in urinalysis results;
11. Patient has acceptable coagulation status as indicated by a Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) within 15% of normal limits;
12. Eastern Cooperative Oncology Group (ECOG) ≤ 2

Exclusion Criteria:

Subjects are ineligible for enrollment if they meet any of the following exclusion criteria:

1. Clinical evidence of deep vein thrombosis (DVT), pulmonary embolism (PE) or other known thromboembolic (TE) event present during the screening period;
2. Any prior history of cerebrovascular accident, transient ischemic attack, or pre-existing carotid artery disease.
3. Known allergy to hyaluronidase;
4. Current use of megestrol acetate (use within 10 days of Day 1);
5. Contraindication to heparin including prior heparin induced thrombocytopenia (HIT), recent CNS bleed; intracranial or spinal lesion at high risk for bleeding; severe platelet dysfunction; recent major operation at high risk for bleeding; underlying hemorrhagic coagulopathy; high risk for falls; potential need for spinal anesthesia/lumbar puncture; active bleeding;
6. Women currently pregnant or breastfeeding;
7. Intolerance to dexamethasone;
8. Inability to comply with study and follow-up procedures as judged by the Investigator;
9. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy;
10. Patient has known infection with HIV, hepatitis B, or hepatitis C;
11. Patient has a history of allergy or hypersensitivity to any of the agents they are supposed to receive (or to any of the excipients for those agents);
12. Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug, these can include New York Heart Association Functional Class ≥ 3, myocardial infarction within the past 12 months before screening, pre-existing atrial fibrillation, symptomatic COPD.
13. Patient is unwilling or unable to comply with study procedures.

Primary outcomes:
measure: Number of Participants with Treatment Related Adverse Events (AEs)
timeFrame: Up to 8 Weeks After the End of Treatment
Secondary outcomes:
measure: Overall Tumor Response Rate
timeFrame: Change from Baseline through 8 Weeks After End of Radiation Therapy
measure: Conversion to Resectability Rate
timeFrame: Up to 8 Weeks After End of Radiation Therapy
measure: Carcinoembryonic Antigen (CEA) Response
timeFrame: Change from Day 1 through 8 Weeks After End of Treatment
measure: CA 19-9 Response
timeFrame: Change from Day 1 through 8 Weeks After End of Treatment
measure: Determine the Maximum or Peak Plasma PEGPH20 Concentration (cmax) at End of Infusion
timeFrame: At Specific Timepoints from Day 1 through Day 39 During Treatment
measure: Determine Plasma PEGPH20 Area Under the Curve (AUC) After Day 1 PEGPH20 Infusion
timeFrame: At Specific Timepoints from Day 1 through Day 39 During Treatment
measure: Determine the Maximum or Peak Plasma Hyaluronan Concentration (cmax) After First Dose of PEGPH20
timeFrame: At Specific Timepoints from Day 1 through Day 39 During Treatment
measure: Determine Plasma Hyaluronan Area Under Effect Curve (AUEC) After First Dose of PEGPH20
timeFrame: At Specific Timepoints from Day 1 through Day 39 During Treatment
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Scripps Cancer Center
state: California
Study officials:
affiliation: Scripps Health/Scripps Clinic
name: Darren S Sigal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baumgartner G, Gomar-Hoss C, Sakr L, Ulsperger E, Wogritsch C. The impact of extracellular matrix on the chemoresistance of solid tumors--experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy. Cancer Lett. 1998 Sep 11;131(1):85-99.
citation: Hingorani S, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotskyet EM, et al. Final Results of a Phase 1b Study of Gemcitabine Plus PEGPH20 in Patients With Stage IV Previously Untreated Pancreatic Cancer. ASCO 2015 Gastrointestinal Cancers Symposium, Poster Abstract 359.
citation: Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011 Nov 1;29(31):4105-12. doi: 10.1200/JCO.2011.34.8904. Epub 2011 Oct 3.
citation: Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol. 2001;18(4):243-59. doi: 10.1385/MO:18:4:243.
citation: Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer. 2013 Jan 15;108(1):1-8. doi: 10.1038/bjc.2012.569. Epub 2013 Jan 8.
citation: Li X, Jiang P, Symons R, et al. Pegylated human recombinant hyaluronidase PH20 reduces solid tumor hypoxia [abstract]. Cancer Res 2012; 72(8 Suppl): Abstract 3796.
citation: Li X. PEGylated human recombinant hyaluronidase (PEGPH20) removes peritumoral hyaluronan and increases the efficacy of chemotherapy and radiotherapy in an experimental brain metastasis model [abstract]. Cancer Res 2009; 69 (9 Suppl): Abstract 262.