Trial to Evaluate Safety and Tolerability of GP-2250 in Combination With Gemcitabine

• Sponsor: Geistlich Pharma AG
• Collaborator: Translational Drug Development
• Information provided by (Responsible Party): Geistlich Pharma AG

Study Description

Brief Summary:

This trial will consist of 2 parts. Phase 1 will use a Bayesian Optimal Interval (BOIN) dose escalation design of GP-2250 as intravenous single-dose monotherapy, followed by combination therapy with gemcitabine in subjects with advanced pancreatic cancer. A Simon Two-Stage Design (Phase 2) will follow this to assess preliminary clinical activity of GP-2250 in combination with gemcitabine at the recommended Phase 2 dose (RP2D) in subjects with advanced pancreatic cancer previously treated with FOLFIRINOX but never exposed to therapeutic gemcitabine

Condition or disease	Intervention/treatment	Phase
Pancreatic Cancer, Adult	Drug: GP-2250	Phase 1; Phase 2

Detailed Description:

In Phase 1 of the study, the dose-limiting toxicity (DLT) assessment period will be 5 weeks---one-week run-in at each dose level of intravenous GP-2250 monotherapy followed by a full cycle of GP-2250 plus gemcitabine (3 weeks on and 1 week off). Single-subject cohorts will be enrolled until the occurrence of the first DLT, at which point cohorts will be expanded to 3 subjects. If there are no DLTs observed within the first 3 single subject cohorts, there will be an expansion to 3 subject cohorts beginning with Cohort#4. Between single-subject cohorts, dose escalation increments of GP-2250 will be 100%. Beginning with the Cohort#4 further dose escalation increments between cohorts will be 35% to 45%. Subjects may continue to receive treatment until disease progression by Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 criteria, clinical disease progression as assessed by the Investigator, development of a DLT (in Phase 1) or unacceptable toxicity, the subject requests withdrawal, the subject meets one of the criteria for treatment discontinuation, the Investigator determines the risks outweigh the benefits of continuing therapy, withdrawal of subject consent, or closure of the trial by the Sponsor.

In Phase 2, subjects will receive weekly doses of GP-2250 in combination with a standard dose of gemcitabine for 3 consecutive weeks (3 weeks on therapy and 1 week off). A Simon Two-Stage design will be used. In the first stage, 10 subjects will be enrolled. If at least 2 responses are observed, an additional 19 subjects will be enrolled. If at the end of the Phase 2 stage of the trial at least 6/29 responders are observed, it can be concluded that the response rate (RR) with GP 2250+gemcitabine is consistent with that of approximately 30%. Subjects may continue to receive treatment until withdrawn by the Investigator, the subject requests withdrawal, unacceptable toxicity occurs, the subject meets one of the criteria for treatment discontinuation, or disease progression, or closure of the trial by the sponsor.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	54 participants
Intervention Model:	Single Group Assignment
Intervention Model Description:	Bayesian Optimal Interval (BOIN); Simon 1 and 2
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1/2 Trial of GP-2250 in Combination With Gemcitabine in Pancreatic Adenocarcinoma After FOLFIRINOX Chemotherapy
Actual Study Start Date :	January 14, 2019
Estimated Primary Completion Date :	December 15, 2020
Estimated Study Completion Date :	February 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: GP-2250 Monotherapy; GP-2250 in doses of 250 mg up to 30 grams intravenously on Days -7, 1, 8, 15 of a 28 day cycle with gemcitabine 1000 mg/m2 on Days 1, 8, 15 days of the cycle.	Drug: GP-2250; GP-2250 monotherapy for pharmacokinetics; GP-2250 plus gemcitabine for tolerability and biomarker assessments; Other Name: gemcitabine

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: 12-24 months ]
   Dose Limiting Toxicity - dose at which toxicity causes cessation of dose escalations.

Secondary Outcome Measures :

1. Carbohydrate Antigen 19-9 (CA-19-9) [ Time Frame: 12-24 months ]
   A type of antigen released by pancreatic cancer cells and usually changes as disease progression or regressions occurs. Measurement of changes, if any, will be assessed in each patient.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

Informed Consent:

1. Capable of giving signed informed consent as described in Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

   Age:

2. Male and female subjects age > 18 years at the time of trial entry. Type of Subject and Disease Characteristics
3. Histologically or cytologically confirmed advanced unresectable or metastatic pancreatic adenocarcinoma
4. Subjects should be eligible to receive gemcitabine monotherapy for the treatment of their pancreatic cancer per the judgment of the Investigator
5. Subjects must have documented disease progression while receiving or within 3 months of completing prior treatment with FOLFIRINOX.
6. Subjects must have at least one RECIST Version 1.1 defined measurable tumor lesion
7. Subjects must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1.
8. Subjects with known central nervous system metastasis must have undergone brain targeted treatment and must be asymptomatic or radiographically and clinically stable (including not requiring steroids or anti-seizure medications) for at least 4 weeks prior to enrollment.
9. All subjects must consent to provide archived tumor specimens for biomarker studies.

10. Subjects must have adequate organ function as indicated by the following laboratory values:

    1. Absolute neutrophil count (ANC) ≥ 1,500 /mL
    2. Platelets ≥ 100,000 / mL
    3. Hemoglobin ≥ 9 g/dL
    4. Serum creatinine ≤ 1.5 X upper limit of normal (ULN)
    5. Serum total bilirubin ≤ 1.5 × ULN
    6. Aspartate aminotransferase (AST), (Serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT), and (Serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × ULN OR ≤ 5 × ULN for subjects with liver metastasis
    7. International Normalized Ratio (INR) and/or Prothrombin Time (PT) ≤ 1.5 × ULN
    8. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN
    9. Serum Albumin ≥ 3 gm/dL
11. Female subjects of childbearing potential (woman of childbearing potential [WOCBP]) must have a negative serum pregnancy test.

12. Subjects must use adequate contraception for the duration of the trial:

    1. Male subjects must agree to use a highly effective contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 3 months after the last dose of trial intervention and refrain from donating sperm during this period
    2. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

Not a WOCBP:

OR A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of trial intervention.

Exclusion Criteria:

Medical Conditions:

1. For Phase 2, diagnosis of any active malignancy other than pancreatic cancer within the past 2 years (not including non-melanoma skin carcinoma, ductal carcinoma in situ of the breast, or carcinoma in situ of uterine cervix treated with curative intent).

2. Any other medical, psychiatric, or social condition deemed by the Investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate and participate in the trial, or which would interfere with the interpretation of the results.

   Prior/Concomitant Therapy:

3. Prior exposure to gemcitabine (except when used as a radiosensitizer at least 6 months prior to enrollment).

4. Any chemotherapy administered within 3 weeks or 5 half-lives (whichever is shorter) before first dose of GP-2250; other anti-cancer therapy (including surgery, radiotherapy, immunotherapy, hormone therapy, or targeted therapy) administered within 4 weeks or 5 half-lives (whichever is shorter) before the first dose of GP-2250; or within 6 weeks in the case of certain therapies (mitomycin C and nitrosoureas).

   Prior/Concurrent Clinical Trial Experience:

5. Investigational therapy administered within 4 weeks before the first dose of GP-2250.

Contacts and Locations

Contacts

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Contact: James C Costin, MD	12154508698	jccmd44@gmail.com
Contact: Thomas Mueller, PhD	+41414926808	thomas.mueller@geistlich.ch

Locations

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United States, Michigan
Quest Research Institute	Recruiting
Farmington Hills, Michigan, United States, 48334
Contact: Laura Nadeau, MD 248-267-6569 laura@questri.com

Sponsors and Collaborators

Geistlich Pharma AG

Translational Drug Development

Investigators

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Study Chair:	Manuel Hildago, MD	Beth Israel Deaconess, Harvard

More Information

Publications of Results:

Buchholz M, Majchrzak-Stiller B, Hahn S, Vangala D, Pfirrmann RW, Uhl W, Braumann C, Chromik AM. Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo. BMC Cancer. 2017 Mar 24;17(1):216. doi: 10.1186/s12885-017-3204-x.

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Responsible Party:	Geistlich Pharma AG
ClinicalTrials.gov Identifier:	NCT03854110 History of Changes
Other Study ID Numbers:	GP-2250-1001
First Posted:	February 26, 2019
Last Update Posted:	February 27, 2019
Last Verified:	February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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

Keywords provided by Geistlich Pharma AG:

Disease progression on Folfirinox

Additional relevant MeSH terms:

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Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Carcinoma; Digestive System Diseases; Endocrine System Diseases	Gemcitabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs