Clinical trial NCT04511039: Trifluridine/Tipiracil and Talazoparib for the Treatment of Patients With Locally Advanced or Metastatic Colorectal or Gastroesophageal Cancer
Official title: A Phase I Study of Trifluridine/ Tipiracil Plus the Poly (ADP) Ribose Polymerase Inhibitor Talazoparib in Advanced Cancers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: 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
Lead sponsor: Roswell Park Cancer Institute
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2020-08-12
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics (PK) and pharmacodynamic (PD) markers of activity.

II. To evaluate the preliminary antineoplastic efficacy of the combination.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed CRC or EGC adenocarcinoma that is locally advanced or metastatic (Cohort A); histologically or cytologically confirmed p53mt/RASonc (Cohort B1) or p53mt/RASwt CRC (Cohort B2) that is locally advanced or metastatic. Patients with adenocarcinoma histology only are allowed to participate.
* 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 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 day -14 (Dose Escalation, Cohort A) or Cycle 1 day 1 (Dose Expansion, Cohorts B1 and B2) or 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 day -14 (Dose Escalation, Cohort A) or Cycle 1 Day 1 (Dose Expansion, Cohorts B1 and B2.
* 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

Primary outcomes:
measure: Incidence of Adverse Events
timeFrame: after each cycle of treatment ( 1 cycle = 14 days)
measure: Maximum tolerated dose/ recommended phase II dose
timeFrame: Up to 14 days
Secondary outcomes:
measure: Plasma Concentration (Cmax)
timeFrame: Day -13 post dose
measure: Plasma Concentration (Cmax)
timeFrame: day -14 pre dose
measure: Plasma Concentration (Cmax)
timeFrame: day -14 post dose
measure: Plasma Concentration (Cmax)
timeFrame: day -13 pre dose
measure: Overall Response Rate (ORR)
timeFrame: Up to 3 years
measure: CEA response rate (colorectal cancer patients)
timeFrame: Up to 3 years
measure: Progression Free Survival (PFS)
timeFrame: From treatment until disease progression UP to 3 years
measure: Overall Survival (OS)
timeFrame: From treatment until death or up to 3 years
measure: Progressive Disease Assessment (PD)
timeFrame: Up to 3 years
measure: Number of subjects with DNA damage response
timeFrame: Up to 28 days prior to first drug dose, on treatment and between cylce 1-day 8 and cycle 1 day 12
Other outcomes:
Locations:
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
Study officials:
affiliation: Roswell Park Cancer Institute
name: Christos Fountzilas, MD
role: PRINCIPAL_INVESTIGATOR
References: