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Trifluridine/Tipiracil and Talazoparib for the Treatment of Patients With Locally Advanced or Metastatic Colorectal or Gastroesophageal Cancer

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ClinicalTrials.gov Identifier: NCT04511039
Recruitment Status : Not yet recruiting
First Posted : August 12, 2020
Last Update Posted : March 16, 2021
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase I trial investigates the side effects and best dose of talazoparib when given together with trifluridine/tipiracil for the treatment of patients with colorectal or gastroesophageal cancer that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Drugs used in the chemotherapy, such as trifluridine/tipiracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving talazoparib with trifluridine/ tipiracil may inhibit certain enzymes in the cells that are responsible for tumor cell growth.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Clinical Stage III Gastroesophageal Junction Adenocarcinoma Clinical Stage IV Gastroesophageal Junction Adenocarcinoma Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma A Locally Advanced Colorectal Carcinoma Locally Advanced Gastroesophageal Junction Adenocarcinoma Metastatic Colorectal Adenocarcinoma Metastatic Gastroesophageal Junction Adenocarcinoma Pathologic Stage III Gastroesophageal Junction Adenocarcinoma Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 Stage III Colorectal Cancer AJCC v8 Stage IIIA Colorectal Cancer AJCC v8 Stage IIIB Colorectal Cancer AJCC v8 Stage IIIC Colorectal Cancer AJCC v8 Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Drug: Trifluridine and Tipiracil Hydrochloride Drug: Talazoparib Tosylate Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of trifluridine and tipiracil hydrochloride (trifluridine/tipiracil [FTD/TPI]) in combination with talazoparib tosylate (talazoparib) in patients with advanced colorectal (CRC) or gastroesophageal (EGC) adenocarcinoma.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Trifluridine/ Tipiracil Plus the Poly (ADP) Ribose Polymerase Inhibitor Talazoparib in Advanced Cancers
Estimated Study Start Date : April 1, 2021
Estimated Primary Completion Date : April 1, 2023
Estimated Study Completion Date : April 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Arm
Patients receive trifluridine/tipiracil PO BID and talazoparib tosylate PO QD on days 1-5. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Drug: Trifluridine and Tipiracil Hydrochloride
Given PO
Other Names:
  • 733030-01-8
  • Lonsurf
  • TAS 102,
  • Thymidine
  • Tipiracil Hydrochlorid Mixture with Trifluridine
  • Trifluridine/Tipiracil
  • Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102

Drug: Talazoparib Tosylate
Given PO
Other Name: Talzenna




Primary Outcome Measures :
  1. Incidence of Adverse Events [ Time Frame: after each cycle of treatment ( 1 cycle = 14 days) ]
    All adverse events will be evaluated using Common Terminology Criteria for All Adverse Events (CTCAE) version (v.) 5.

  2. Maximum tolerated dose/ recommended phase II dose [ Time Frame: Up to 14 days ]
    Will utilize the keyboard design - a novel model- assisted dose-finding method to find the maximum tolerated dose


Secondary Outcome Measures :
  1. Plasma Concentration (Cmax) [ Time Frame: Day -13 post dose ]
    The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose

  2. Plasma Concentration (Cmax) [ Time Frame: day -14 pre dose ]
    The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose

  3. Plasma Concentration (Cmax) [ Time Frame: day -14 post dose ]
    The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose

  4. Plasma Concentration (Cmax) [ Time Frame: day -13 pre dose ]
    The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose

  5. Overall Response Rate (ORR) [ Time Frame: Up to 3 years ]
    Will be summarized using frequencies and relative frequencies.

  6. CEA response rate (colorectal cancer patients) [ Time Frame: Up to 3 years ]
    ill be summarized using frequencies and relative frequencies. .

  7. Progression Free Survival (PFS) [ Time Frame: From treatment until disease progression UP to 3 years ]
    Will be summarized using standard Kaplan-Meier methods

  8. Overall Survival (OS) [ Time Frame: From treatment until death or up to 3 years ]
    Will be summarized using standard Kaplan-Meier methods

  9. Progressive Disease Assessment (PD) [ Time Frame: Up to 3 years ]
  10. Number of subjects with DNA damage response [ Time Frame: Up to 28 days prior to first drug dose, on treatment and between cylce 1-day 8 and cycle 1 day 12 ]
    Tumor biopsies will be summarized by dose level and time-point using means and standard deviations.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Histologically or cytologically confirmed CRC or EGC adenocarcinoma that is locally advanced or metastatic
  • Has received at least one prior line of therapy with progression or intolerance
  • Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Life expectancy >= 3 months by investigator assessment
  • Hemoglobin >= 9 g/dL
  • Absolute neutrophil count >= 1500/mm^3
  • Platelet count >= 100,000/mm^3 without transfusion or growth factor support
  • Creatinine < 1.5 upper limit of normal (ULN) or creatinine clearance > 60 mL/min
  • Total bilirubin < 1.5 x ULN
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN or < x 5 ULN in the presence of liver metastasis
  • Albumin > 3 g/dL
  • Ability to swallow oral medications
  • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Systemic antineoplastic therapy within 2 weeks prior to initiation of FTD/TPI run-in phase (within the past 6 weeks if this treatment is mitomycin C or nitrosourea)
  • Radiotherapy within the past 2 weeks excluding palliative radiotherapy to painful bone lesions
  • Prior treatment with PARP inhibitor or FTD/TPI
  • Any condition that in the investigator's opinion can limit absorption of FTD/TPI or talazoparib from the gastrointestinal (GI) tract
  • Gastrointestinal obstruction (without diversion) or perforation within 4 weeks from initiation of FTD/TPI run-in
  • Refractory ascites (requiring weekly or more frequent paracentesis or permanent indwelling peritoneal catheter)
  • Untreated central nervous system (CNS) disease. Patients with leptomeningeal disease are ineligible but patients with treated, stable CNS metastasis for at least 4 weeks are allowed to participate
  • Significant cardiac disease defined as congestive heart failure stage III or IV (New York Heart Association [NYHA]), acute coronary event, cerebrovascular event, peripheral arterial embolic event, venous thromboembolic event (pulmonary embolism or lower extremity deep vein thrombosis), or ventricular arrhythmia within the past 3 months
  • Other malignancy requiring active therapy
  • Presence of toxicities from prior therapy of grade 2 or higher
  • Active infection requiring antibiotic therapy
  • Known human immunodeficiency virus (HIV) or hepatitis B infection or untreated hepatitis C infection. Patients with treated hepatitis C infection and undetectable viral load are allowed to participate
  • Any history of myelodysplastic syndrome, acute leukemia, or bone marrow transplant
  • Pregnant or nursing female participants
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04511039


Contacts
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Contact: Christos Fountzilas, MD 716-845-8974 Christos.Fountzilas@roswellpark.org

Sponsors and Collaborators
Roswell Park Cancer Institute
Pfizer
Investigators
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Principal Investigator: Christos Fountzilas, MD Roswell Park Cancer Institute
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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT04511039    
Other Study ID Numbers: I 650120
First Posted: August 12, 2020    Key Record Dates
Last Update Posted: March 16, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Adenocarcinoma
Esophageal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Head and Neck Neoplasms
Esophageal Diseases
Trifluridine
Talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites
Antiviral Agents
Anti-Infective Agents