PEGPH20 Plus Gemcitabine With Radiotherapy in Patients With Localized, Unresectable Pancreatic Cancer

NCT ID: NCT02910882

Last Updated: 2019-04-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 4 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-03
• Study Completion Date: 2018-08-31

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.

Conditions

Pancreatic Adenocarcinoma Non-resectable

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Single Arm

Cohort I (PEGPH20 Dose Escalation + Gemcitabine and Concurrent Radiotherapy), First 3 Patients:

An abbreviated sequential dose escalation schema for the first 3 patients (each subsequent patient will be accrued only after no dose limiting toxicities are found in the first 2 weeks of concurrent therapy for the previous patient).

Intravenous (IV) PEGPH20, per dose escalation guidelines for first 3 patients; Intravenous (IV) Gemcitabine (Standard Regimen); Radiotherapy (Standard Regimen);

Cohort II (PEGPH20 + Gemcitabine and Concurrent Radiotherapy), Patients 4 - 10:

IV PEGPH20, per dosing level determined in dose escalation (Cohort I); IV Gemcitabine (Standard Regimen); Radiotherapy (Standard Regimen);

Group Type: EXPERIMENTAL

PEGylated Recombinant Human Hyaluronidase (PEGPH20)

Intervention Type: DRUG

PEGPH20 Dosing (Cohort I, Dose Escalation, First 3 patients): Administered as an IV infusion over 10 minutes (+/- 2 Minutes), approximately 1mL/minute:

Dose level 1 - 1 mcg/kg; Dose level 2 - 1.6 mcg/kg; Dose level 3 - 3 mcg/kg.

PEGPH20 Dosing (Cohort II, Patients 4-10): Administered at a dose of 3 mcg/kg as an IV infusion over 10 minutes (+/- 2 Minutes), approximately 1mL/minute.

Dosing Schedule: Twice per week beginning Day #1 for 8 doses, then weekly until end of radiotherapy.

Gemcitabine

Intervention Type: DRUG

Gemcitabine Dosing: Administered at a dose of 600 mg/m2 as an IV infusion over 30 - 60 minutes with standard antiemetic pre-medication. If administered on PEGPH20 day, Gemcitabine will be infused 2-4 Hours after PEGPH20 infusion is completed.

Dosing Schedule: Weekly, beginning Day #2, per standard regimen.

Radiation

Intervention Type: RADIATION

Radiotherapy, beginning Day #2, delivered at 1.8 Gy per fraction, 5 fractions per week (Monday - Friday), until a total dose of 50.4 to 54 Gy for up to 6 Weeks.

Interventions

PEGylated Recombinant Human Hyaluronidase (PEGPH20)

PEGPH20 Dosing (Cohort I, Dose Escalation, First 3 patients): Administered as an IV infusion over 10 minutes (+/- 2 Minutes), approximately 1mL/minute:

Dose level 1 - 1 mcg/kg; Dose level 2 - 1.6 mcg/kg; Dose level 3 - 3 mcg/kg.

PEGPH20 Dosing (Cohort II, Patients 4-10): Administered at a dose of 3 mcg/kg as an IV infusion over 10 minutes (+/- 2 Minutes), approximately 1mL/minute.

Dosing Schedule: Twice per week beginning Day #1 for 8 doses, then weekly until end of radiotherapy.

Intervention Type: DRUG

Gemcitabine

Gemcitabine Dosing: Administered at a dose of 600 mg/m2 as an IV infusion over 30 - 60 minutes with standard antiemetic pre-medication. If administered on PEGPH20 day, Gemcitabine will be infused 2-4 Hours after PEGPH20 infusion is completed.

Dosing Schedule: Weekly, beginning Day #2, per standard regimen.

Intervention Type: DRUG

Radiation

Radiotherapy, beginning Day #2, delivered at 1.8 Gy per fraction, 5 fractions per week (Monday - Friday), until a total dose of 50.4 to 54 Gy for up to 6 Weeks.

Intervention Type: RADIATION

Other Intervention Names

PEGylated rHuPH20; Gemzar

Eligibility Criteria

Inclusion Criteria

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

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.

• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Scripps Health

OTHER

Sponsor Role: lead

Responsible Party

Darren Sigal, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Darren S Sigal, MD

Role: PRINCIPAL_INVESTIGATOR

Scripps Health/Scripps Clinic

Locations

Scripps Cancer Center

La Jolla, California, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 9839623 (View on PubMed)

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

PMID: 21969502 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11918451 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23299539 (View on PubMed)

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

Other Identifiers

PEGPH20-GEM-XRT

Identifier Type: -

Identifier Source: org_study_id