This phase Ib trial is to find out the best dose, possible benefits and/or side effects of talazoparib when given in combination with palbociclib, axitinib, or crizotinib in treating patients with solid tumors that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). PARPs are proteins that help repair damaged DNA, the genetic material that serves as the body's instruction book. PARP inhibitors, such as talazoparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Palbociclib, axitinib, and crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving talazoparib in combination with palbociclib, axitinib, or crizotinib may help control locally advanced or metastatic solid tumors.
PRIMARY OBJECTIVES: I. To determine the safety and tolerability, and establish the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of the combination of talazoparib tosylate (talazoparib) with palbociclib isethionate (palbociclib) (Arm A), axitinib (Arm B), and crizotinib (Arm C) in patients with advanced solid tumors. II. To assess the safety and toxicity profile of the combination of talazoparib with palbociclib (Arm A), axitinib (Arm B), and crizotinib (Arm C). SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetic and pharmacodynamic profile of the combination of talazoparib with palbociclib (Arm A), axitinib (Arm B), and crizotinib (Arm C). II. To obtain a preliminary assessment of the antitumor activity of the combination of talazoparib with palbociclib (Arm A), axitinib (Arm B), and crizotinib (Arm C). III. To assess predictive biomarkers of response and resistance to the combination of talazoparib with palbociclib (Arm A), axitinib (Arm B), and crizotinib (Arm C). OUTLINE: This is a phase I, dose-escalation study. Patients are assigned to 1 of 3 arms. ARM A: Patients receive talazoparib orally (PO) once daily (QD) on days 1-21 or 1-28 and palbociclib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patient may continue treatment even if there is progression of disease as long as the patient remains clinically stable, per the treating physician's discretion. ARM B: Patients receive talazoparib PO QD on days 1-28 and axitinib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patient may continue treatment even if there is progression of disease as long as the patient remains clinically stable, per the treating physician's discretion. ARM C: Patients receive talazoparib PO QD on days 1-28 and crizotinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patient may continue treatment even if there is progression of disease as long as the patient remains clinically stable, per the treating physician's discretion. After the completion of study treatment, patients are followed up for 90 days and then every 12 weeks until progression of disease, receipt of another cancer drug, or for another two years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
111
M D Anderson Cancer Center
Houston, Texas, United States
RECRUITINGIncidence of adverse events
Incidence and severity of adverse events and serious adverse events in patients being treated with the combination of talazoparib with palbociclib (Arm A), axitinib (Arm B), and crizotinib (Arm C). Severity of adverse events (AEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Tabulations will be produced for safety parameters.
Time frame: Up to 30 days after the last investigational product administration
Incidence of dose limiting toxicities
Incidence of dose limiting toxicities of the combination of talazoparib with palbociclib (Arm A), axitinib (Arm B), and crizotinib (Arm C) will be assessed. Severity of AEs will be graded according to the NCI CTCAE version 5.0.
Time frame: Up to 30 days after the last investigational product administration
Plasma pharmacokinetic (PK) parameters (maximum plasma concentration)
Plasma pharmacokinetic parameters including the maximum plasma concentration. Descriptive statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by trial arm, dose, cycle and day. Individual curves of serum concentration of each study drug versus time will be presented on log- and linear scale for all patients in the PK population. Furthermore, maximum and trough serum concentrations for the period from first dose to end of treatment will be presented on linear scale individual plots.
Time frame: Up to 2 years
Plasma pharmacokinetic (PK) parameters (time to maximum plasma concentration)
Plasma pharmacokinetic parameters including the time to maximum plasma concentration Descriptive statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by trial arm, dose, cycle and day. Individual curves of serum concentration of each study drug versus time will be presented on log- and linear scale for all patients in the PK population. Furthermore, maximum and trough serum concentrations for the period from first dose to end of treatment will be presented on linear scale individual plots.
Time frame: Up to 2 years
Plasma pharmacokinetic (PK) parameters (area under the plasma concentration)
Plasma pharmacokinetic parameters including the area under the plasma concentration versus time curve will be estimated using non-compartmental analysis. Descriptive statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by trial arm, dose, cycle and day. Individual curves of serum concentration of each study drug versus time will be presented on log- and linear scale for all patients in the PK population. Furthermore, maximum and trough serum concentrations for the period from first dose to end of treatment will be presented on linear scale individual plots.
Time frame: Up to 2 years
Plasma pharmacokinetic parameters (Ctrough)
Plasma pharmacokinetic parameters including the Ctrough. Descriptive statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by trial arm, dose, cycle and day. Individual curves of serum concentration of each study drug versus time will be presented on log- and linear scale for all patients in the PK population. Trough serum concentrations for the period from first dose to end of treatment will be presented on linear scale individual plots.
Time frame: Up to 2 years
Plasma pharmacokinetic parameters (maximum)
Plasma pharmacokinetic parameters including the maximum. Descriptive statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by trial arm, dose, cycle and day. Individual curves of serum concentration of each study drug versus time will be presented on log- and linear scale for all patients in the PK population. Maximum serum concentrations for the period from first dose to end of treatment will be presented on linear scale individual plots.
Time frame: Up to 2 years
Clinical benefit rate
Will assess antitumor activity by clinical benefit rate complete response (CR) + partial response (PR) + stable disease \> 4 months per Response Evaluation Criteria in Solid Tumors (RECIST) version(v) 1.1.
Time frame: Up to 2 years
Duration of response
Estimated using Kaplan-Meier methods. A 95% confidence interval of response rate will be estimated based on the binomial distribution.
Time frame: Up to 2 years
Objective response
Objective response is defined as a best overall response of CR or PR per RECIST v1.1.
Time frame: Up to 2 years
Progression free survival
Estimated using Kaplan-Meier methods. A 95% confidence interval of response rate will be estimated based on the binomial distribution.
Time frame: Up to 2 years
Overall survival
Estimated using Kaplan-Meier methods. A 95% confidence interval of response rate will be estimated based on the binomial distribution.
Time frame: Up to 2 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.