A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT04229004
• Recruitment Status: Not yet recruiting
• First Posted: January 14, 2020
• Last Update Posted: January 31, 2020
• Sponsor: Pancreatic Cancer Action Network
• Information provided by (Responsible Party): Pancreatic Cancer Action Network

Study Description

Brief Summary:

Precision Promise is a multi-center, seamless Phase 2/3 platform trial designed to evaluate multiple regimens in metastatic pancreatic cancer.

Primary Objectives

• To compare each investigational arm versus standard of care (SOC) for superiority in overall survival in 1st and/or 2nd line metastatic pancreatic cancer patients and determine which, if any, patients benefit from each investigational arm.

Secondary Objectives

• To determine short and long-term safety signals of each investigational arm in pancreatic cancer patients vs. SOC.
• To determine progression-free survival (PFS) for each investigational arm vs. SOC.
• Rates of overall response, CR, and PR; duration of overall response, CR or PR (whichever occurs first).
• Rate of clinical benefit; duration of clinical benefit.

Condition or disease	Intervention/treatment	Phase
Metastatic Pancreatic Cancer; Metastatic Pancreatic Adenocarcinoma	Drug: Gemcitabine combined with nab-paclitaxel; Drug: Dose -SM-88; Drug: Dose -mFOLFIRINOX	Phase 3

Detailed Description:

Precision Promise is a multi-center, seamless Phase 2/3 platform trial designed to evaluate multiple regimens in metastatic pancreatic cancer. The goal of the platform is to find effective therapies for pancreatic cancer. The platform will rapidly and efficiently test multiple novel drugs and combinations compared to standard of care therapy in first and second metastatic patients. Bayesian response-adaptive randomization will be used to assign patients to arms based on their performance in subtypes of the disease. The primary endpoint is overall survival.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 825 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Precision Promise Platform Trial for Metastatic Pancreatic Cancer
• Estimated Study Start Date: January 31, 2020
• Estimated Primary Completion Date: January 20, 2024
• Estimated Study Completion Date: February 20, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Gemcitabine combined with nab-paclitaxel; The following are recommended parameters for infusion timing and sequence, although institutional variation in the administration of the regimen are permitted as long as drug dosing and modification guidelines are followed.	Drug: Gemcitabine combined with nab-paclitaxel; Nab-paclitaxel is infused over 30-40 min on days 1, 8, 15 of each 28-day cycle. Gemcitabine is infused over 30 min, immediately after completion of nab-paclitaxel infusion, on days 1, 8, 15 of each 28-day cycle If one of the chemotherapy medications is held, the other study medications may be given. Doses should be re-adjusted if the subject's BSA changes by +/- >10%. If the subject's BSA changes by <10%, no adjustment is necessary unless the site has a standard procedure to adjust doses based upon current BSA according to institutional guidelines.
Experimental: SM-88; 460 mg (2 capsules) twice daily of a 28-day cycle along with the administration of methoxsalen, phenytoin and sirolimus. All four agents (SM-88, methoxsalen, phenytoin, and sirolimus) should be dosed with approximately 240 mL (8 fl. oz.) of water in the morning. All four agents should be taken together consistently. SM-88 used with MPS should ideally be taken approximately 1 hour before or 2 hours after a meal.	Drug: Dose -SM-88; 460 mg (2 capsules) twice daily of a 28-day cycle along with the administration of methoxsalen, phenytoin and sirolimus.
Active Comparator: mFOLFIRINOX; Oxaliplatin 85 mg/m2, Leucovorin 400 mg/m2, Irinotecan 150 mg/m2, 5-Fluorouracil 2400 mg/m2 46-48 hour infusion	Drug: Dose -mFOLFIRINOX; The following are recommended parameters for infusion timing and sequence, although institutional variation in the administration of the regimen are permitted, as long as drug dosing and modification guidelines are followed. Oxaliplatin and leucovorin are administered concurrently over 30-120 minutes, followed by irinotecan over 30-90 minutes, followed by the infusion of 5-flurouracil. If one of the chemotherapy medications is held, the other study medications may be given. Doses should be re-adjusted if the subject's BSA changes by +/- >10%. If the subject's BSA changes by <10%, no adjustment is necessary unless the site has a standard procedure to adjust doses based upon current BSA according to institutional guidelines.

Outcome Measures

Primary Outcome Measures :

1. Overall Survival [ Time Frame: 0 weeks ]
   Overall survival (OS) is defined from the time of initiation of treatment until death due to any cause. Subjects still alive at the time of an analysis will be considered censored at their date of last contact.

Secondary Outcome Measures :

1. Progression free survival (PFS) [ Time Frame: From initiation of therapy to clinically determined disease progression or death due to any cause, whichever came first, assessed up to 24 months. ]
   PFS will be presented with probability that the hazard ratio is less than 1.0 as well as the corresponding Kaplan-Meier curves and the log-rank test for the comparison with controls.
2. Performance Status [ Time Frame: From screening through study completion, an average of 2 years. ]
   Changes in Performance Status will be evaluated using the Eastern Cooperative Oncology Group (ECOG) Performance Status, where the highest value is 0 (patient is fully active) and the lowest value is 5 (patient is deceased).
3. Overall Response Rate (ORR) [ Time Frame: From initiation of treatment to clinically determined tumor size reduction for a minimum of 4 weeks ]
   ORR is defined as the portion of subjects on an arm with a tumor size reduction of at least 30%.
4. Duration of Overall Response Rate (ORR) [ Time Frame: From date of first occurrence of a documented objective response to date of clinically determined disease progression or death due to any cause, whichever came first, assessed up to 24 months. ]
   Duration of ORR is defined as the time from the date of response to the date of clinically determined disease progression or death due to any cause.
5. Duration of Clinical Benefit [ Time Frame: From screening through last dose of therapy, assessed up to 24 months. ]
   Duration of Clinical Benefit will be evaluated using a composite of measures including patient reported outcomes (PROs), supportive care regimens, and disease status.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

A subject will be eligible to participate in Precision PromiseSM if all the below inclusion criteria are met:

1. Age ≥ 18 years
2. Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma (PDAC) and eligible for treatment in the first line or second line settings. Note: prior adjuvant or neoadjuvant chemotherapy is permitted if the last dose was >12 months prior and all the other conditions below are met.
3. Radiographically measurable disease of at least one site by computed tomography (CT) scan (or magnetic resonance imaging, if allergic to CT contrast media) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Imaging results must be obtained within the 28-day window, prior to randomization.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

5. Adequate organ function (lab results must be obtained within the 28-day window prior to randomization)

   1. Absolute neutrophil count ≥ 1500/mm3
   2. Hemoglobin ≥ the lower limit of normal (LLN) or 9g/dL
   3. Platelets ≥ 100,000/mm
   4. Serum creatinine ≤ 1.0 x upper limit normal (ULN), or calculated creatinine clearance ≥ 60 mL/min (Cockcroft Gault)
   5. Albumin ≥ 3.0 g/dL
   6. Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x ULN (up to 5 x ULN in presence of liver metastasis).
   7. Total bilirubin ≤ 1.5 x ULN
   8. INR ≤ 1.5 x ULN
6. Consent to provide protocol-mandated tissue and blood samples for diagnostic and research purposes.
7. Able to swallow pills, capsules or tablets.
8. Able to adhere to study visit schedule and other protocol requirements.

9. Females of childbearing potential [defined as a sexually mature woman who (1) has not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)] must:

   1. Have a negative serum or urine pregnancy test (β-human chorionic gonadotropin [β-hCG]) as verified by the study doctor within 14 days prior to randomization.
   2. Commit to complete abstinence from heterosexual contact or agree to use medical doctor-approved contraception throughout the study without interruption while receiving study treatment and for at least 6 months following last dose of study treatment.
10. Males must practice complete abstinence or agree to use a condom (even if he has undergone a successful vasectomy) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following last dose of study treatment.
11. Understands the nature of the study and has agreed to participate by voluntarily signing the IRB approved informed consent.

Exclusion Criteria:

1. A subject will not be eligible to participate in Precision PromiseSM if any of the following criteria are met:

   a) Received any therapy within 28 days (or 5 half-lives, whichever is shorter,) prior to randomization.

2. History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
3. Pre-existing peripheral neuropathy > Grade 1, as defined by CTCAE V 4.03.
4. Known history of hepatitis B, HIV or active hepatitis C infection.
5. Note: HIV testing is not required in the absence of clinical suspicion
6. Serious, non-healing wound, ulcer, bone fracture, or abscess.
7. The inability to swallow pills, capsules or tablets.
8. Subjects who received a combination of two investigational agents as part of first-line therapy (novel + novel) are excluded. Subjects who received one investigational agent or one investigational agent combined with an FDA approved chemotherapy regimen in first line will be allowed to be enrolled in Precision PromiseSM for second line therapy.
9. Any secondary malignancy that required chemotherapy treatment in the past two years
10. History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.
11. QTc > 450 msec if male and QTc > 470 msec if female.
12. Uncontrolled or severe cardiac disease (history of unstable angina, myocardial infarction, coronary stenting, or bypass surgery within the prior 6 months), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia [including atrial flutter/fibrillation], requirement for inotropic support or use of devices for cardiac conditions [pacemakers/defibrillators]).
13. Active, uncontrolled infections (bacterial, viral, or fungal infection(s)) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment (i.e., subjects must be afebrile for > 48 hours off antibiotics).

14. Active, known or suspected autoimmune disease, including systemic lupus erythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa or autoimmune hepatitis.

    a) Subjects with type I diabetes mellitus, hypothyroidism requiring only hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible to participate.

15. Receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the Investigator, increase the risk of serious neutropenic complications.
16. Receipt of live vaccines within 30 days prior to the first dose of study treatment or while on active treatment within the trial. (examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted. However, intranasal influenza vaccines (e.g. Flu-Mist are live attenuated vaccines and are not permitted).
17. Any significant medical condition, laboratory abnormality or psychiatric illness that would limit the subject's ability to comply with study requirements.

18. Subjects that discontinued previous treatment for pancreatic adenocarcinoma due to a treatment-related Grade 3 toxicity.

    1. For toxicity discontinuations < Grade 3, AE(s) must resolve to Grade 1 or baseline in order to be considered eligible for this trial.

Contacts and Locations

Locations

United States, Washington

Virginia Mason Hospital & Seattle Medical Center

Seattle, Washington, United States, 98101

Contact: Vincent Picozzi 206-223-6193 vincent.picozzi@vmmc.org

Contact: Anas Najjar 206-287-6271 anas.najjar@virginiamason.org

Sponsors and Collaborators

Pancreatic Cancer Action Network

More Information

• Responsible Party: Pancreatic Cancer Action Network
• ClinicalTrials.gov Identifier: NCT04229004
• Other Study ID Numbers: PanCAN_Precision Promise
• First Posted: January 14, 2020
• Last Update Posted: January 31, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Adenocarcinoma; Pancreatic Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Gemcitabine; Paclitaxel; Albumin-Bound Paclitaxel; Phenytoin; Methoxsalen; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors