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Phase I Nab-Paclitaxel Plus Gemcitabine With Proton Therapy for Locally Advanced Pancreatic Cancer (LAPC)

Primary Purpose

Locally Advanced Pancreatic Cancer

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Gemcitabine

Hypofractionated Ablative Proton Therapy

About this trial

This is an interventional treatment trial for Locally Advanced Pancreatic Cancer focused on measuring LAPC, Nab-paclitaxel +Gemcitabine, Proton Therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Cytologic or histologic proof of adenocarcinoma of the pancreas.
Nonmetastatic pancreatic cancer. Metastatic disease includes spread to distant (non-regional) lymph nodes, organs, peritoneum and ascites.
Unequivocal radiographic findings contraindicating resection including, but not limited to, solid tumor contact with any of the following: 1) the SMA >180º; 2) the celiac axis >180º; 3) the first jejunal superior mesenteric artery (SMA) branch; 4) unreconstructible superior mesenteric vein (SMV)/portal vein due to tumor involvement or occclusion; 5) the most proximal draining jejunal branch into the SMV.
ECOG Performance Status 0 or 1.
Absolute neutrophil count ≥1,000/mm3
Platelet count ≥100,000/mm3
Creatinine ≤1.5 × upper limit of normal
Calculated creatinine clearance >45 mL/min
Total bilirubin ≤2 mg/dL

Exclusion Criteria:

Patients with resectable or borderline resectable pancreatic cancer are ineligible.
No prior definitive resection of pancreatic cancer.
No prior radiation therapy to the abdomen that would overlap fields required in this study. Prior radiotherapy for other disease is allowed.
No prior chemotherapy except for FOLFIRINOX, Gem-Abrax, or Gem-Cap. A patient may be registered for the trial while undergoing chemotherapy.
Any grade 4 toxicity prior to start of chemoradiotherapy that may be due to induction chemotherapy.
Greater than 2 dose reductions during induction chemotherapy.
Chronic concomitant treatment with strong inhibitors of CYP3A4. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to the start of study treatment. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.
Baseline Grade ≥ 2 neuropathy. Known Gilbert's disease or known homozygosity for UGAT1A1*28 polymorphism.
Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry if they are in childbearing years/premenopausal.
Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with gemcitabine and nab-paclitaxel.
Non-compliance with induction chemotherapy.

Sites / Locations

MedStar Georgetown University HospitalRecruiting
University of Maryland Medical Center/Maryland Proton Treatment CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Pancreatic Proton Therapy With Concurrent Gem + Nab-paclitaxel

Arm Description

Part I: Gemcitabine + nab-paclitaxel: • Administered per institutional standard every 7 days for 3 weeks Part II: Hypofractionated ablative pancreatic proton radiation therapy 67.5 Gy fractions once per day Monday - Friday for 3 weeks, for a total of 15 fractions. Part III: Surgery, if resectable, then adjuvant chemo per discretion of MD or no further therapy OR Chemo per discretion of MD if not resectable

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose of Gemcitabine and nab-Paclitaxel in LAPC patients receiving proton therapy

Maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy for the treatment of locally advanced pancreatic cancer.

Secondary Outcome Measures

Primary Tumor Response in LAPC patients receiving proton therapy with concurrent Gemcitabine and nab-Paclitaxel

Primary tumor response in patients receiving with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy evaluated by CT or MRI

Survival status (disease-free-survival vs. overall survival)

Time to recurrence and site of recurrence in patients with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy (RECIST)

Median Overall Survival of Patients

Median overall survival of patients with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy

R0 Resection

R0 resection rates in patients with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy

Number of adverse events/toxicites reported during and following treatment of concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy

Number of toxicities participants reported by participants during and following treatment of concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy (NIH CTCAE v 4)

Quality of life through and after treatment

Patient reported quality of life impact from receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy using the FACT-Hep questionnaire

Full Information

NCT ID

NCT03652428

First Posted

August 22, 2018

Last Updated

March 1, 2023

Sponsor

University of Maryland, Baltimore

1. Study Identification

Unique Protocol Identification Number

NCT03652428

Brief Title

Phase I Nab-Paclitaxel Plus Gemcitabine With Proton Therapy for Locally Advanced Pancreatic Cancer (LAPC)

Official Title

Phase I Study of Concurrent Nab-Paclitaxel + Gemcitabine With Hypofractionated, Ablative Proton Therapy for Locally Advanced Pancreatic Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 2, 2019 (Actual)

Primary Completion Date

December 31, 2024 (Anticipated)

Study Completion Date

December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Maryland, Baltimore

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine the maximum tolerated dose of the chemotherapy drugs nab-paclitaxel and gemcitabine when combined with hypofractionated ablative proton therapy for the treatment of locally advanced pancreatic cancer. You will receive proton therapy once a day (Monday - Friday) for 3 weeks. Participants will also receive chemotherapy on each Monday of those three weeks.

Detailed Description

The investigators propose a phase I trial to determine the maximum tolerable dose (MTD) and the recommended dose for phase II (RP2D) of concurrent nab-paclitaxel + gemcitabine in combination with ablative IMPT delivered as a fixed dose of 67.5 Gy in 15 fractions daily fractions with 5 fractions per week. In contrast to prior pancreatic cancer studies of chemoradiotherapy which utilized photon RT to treat gross disease and elective lymph nodes (1,2) the proposed study is hypothesized to reduce toxicity risk by limiting highly conformal IMPT to the gross tumor volume. Furthermore, to increase the margin of safety in a manner similar to published data from MDACC (3), the high dose region will be limited to areas at least 5 mm from nearby GI structures (duodenum, small bowel, stomach, etc.). Regions within this area will be treated only to 37.5 Gy in 15 fractions. This dose limitation is also important given that paclitaxel, in addition to increasing systemic efficacy, is a known radiosensitizer (1).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Locally Advanced Pancreatic Cancer

Keywords

LAPC, Nab-paclitaxel +Gemcitabine, Proton Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Pancreatic Proton Therapy With Concurrent Gem + Nab-paclitaxel

Arm Type

Other

Arm Description

Intervention Type

Drug

Intervention Name(s)

Gemcitabine

Other Intervention Name(s)

Nab-Paclitaxel

Intervention Description

see arm description

Intervention Type

Radiation

Intervention Name(s)

Hypofractionated Ablative Proton Therapy

Intervention Description

see arm description

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose of Gemcitabine and nab-Paclitaxel in LAPC patients receiving proton therapy

Description

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

Secondary Outcome Measure Information:

Title

Primary Tumor Response in LAPC patients receiving proton therapy with concurrent Gemcitabine and nab-Paclitaxel

Description

Primary tumor response in patients receiving with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy evaluated by CT or MRI

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

Title

Survival status (disease-free-survival vs. overall survival)

Description

Time to recurrence and site of recurrence in patients with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy (RECIST)

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

Title

Median Overall Survival of Patients

Description

Median overall survival of patients with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

Title

R0 Resection

Description

R0 resection rates in patients with LAPC receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

Title

Number of adverse events/toxicites reported during and following treatment of concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy

Description

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

Title

Quality of life through and after treatment

Description

Patient reported quality of life impact from receiving preoperative concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy using the FACT-Hep questionnaire

Time Frame

Patients will be followed for 12 months after registration or until death, whichever occurs first.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Cytologic or histologic proof of adenocarcinoma of the pancreas. Nonmetastatic pancreatic cancer. Metastatic disease includes spread to distant (non-regional) lymph nodes, organs, peritoneum and ascites. Unequivocal radiographic findings contraindicating resection including, but not limited to, solid tumor contact with any of the following: 1) the SMA >180º; 2) the celiac axis >180º; 3) the first jejunal superior mesenteric artery (SMA) branch; 4) unreconstructible superior mesenteric vein (SMV)/portal vein due to tumor involvement or occclusion; 5) the most proximal draining jejunal branch into the SMV. ECOG Performance Status 0 or 1. Absolute neutrophil count ≥1,000/mm3 Platelet count ≥100,000/mm3 Creatinine ≤1.5 × upper limit of normal Calculated creatinine clearance >45 mL/min Total bilirubin ≤2 mg/dL Exclusion Criteria: Patients with resectable or borderline resectable pancreatic cancer are ineligible. No prior definitive resection of pancreatic cancer. No prior radiation therapy to the abdomen that would overlap fields required in this study. Prior radiotherapy for other disease is allowed. No prior chemotherapy except for FOLFIRINOX, Gem-Abrax, or Gem-Cap. A patient may be registered for the trial while undergoing chemotherapy. Any grade 4 toxicity prior to start of chemoradiotherapy that may be due to induction chemotherapy. Greater than 2 dose reductions during induction chemotherapy. Chronic concomitant treatment with strong inhibitors of CYP3A4. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to the start of study treatment. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment. Baseline Grade ≥ 2 neuropathy. Known Gilbert's disease or known homozygosity for UGAT1A1*28 polymorphism. Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry if they are in childbearing years/premenopausal. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with gemcitabine and nab-paclitaxel. Non-compliance with induction chemotherapy.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jason Molitoris, MD

Phone

410-328-2328

jmolitoris@umm.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Jasmine A Newman, BS

Phone

410-369-5355

jasmine.newman@umm.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jason Molitoris, MD

Organizational Affiliation

University of Maryland/Maryland Proton Treatment Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

MedStar Georgetown University Hospital

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20007

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nicole Villa, MSN, RN

Phone

202-687-2939

nv209@georgetown.edu

First Name & Middle Initial & Last Name & Degree

Keith Unger, MD

Facility Name

University of Maryland Medical Center/Maryland Proton Treatment Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jasmine A Newman, BS

Phone

410-369-5355

jasmine.newman@umm.edu

First Name & Middle Initial & Last Name & Degree

Jason Molitoris, MD

12. IPD Sharing Statement

Citations:

PubMed Identifier

14758134

Citation

Rich T, Harris J, Abrams R, Erickson B, Doherty M, Paradelo J, Small W Jr, Safran H, Wanebo HJ. Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol. 2004 Feb;27(1):51-6. doi: 10.1097/01.coc.0000046300.88847.bf.

Results Reference

background

PubMed Identifier

11560155

Citation

Crane CH, Janjan NA, Evans DB, Wolff RA, Ballo MT, Milas L, Mason K, Charnsangavej C, Pisters PW, Lee JE, Lenzi R, Vauthey JN, Wong A, Phan T, Nguyen Q, Abbruzzese JL. Toxicity and efficacy of concurrent gemcitabine and radiotherapy for locally advanced pancreatic cancer. Int J Pancreatol. 2001;29(1):9-18. doi: 10.1385/IJGC:29:1:09.

Results Reference

background

PubMed Identifier

26972648

Citation

Krishnan S, Chadha AS, Suh Y, Chen HC, Rao A, Das P, Minsky BD, Mahmood U, Delclos ME, Sawakuchi GO, Beddar S, Katz MH, Fleming JB, Javle MM, Varadhachary GR, Wolff RA, Crane CH. Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation. Int J Radiat Oncol Biol Phys. 2016 Mar 15;94(4):755-65. doi: 10.1016/j.ijrobp.2015.12.003. Epub 2015 Dec 11.

Results Reference

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Phase I Nab-Paclitaxel Plus Gemcitabine With Proton Therapy for Locally Advanced Pancreatic Cancer (LAPC)

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