a single arm, phase ib/ii trial of single agent pacritinib in patients with 1q21.3 amplified solid tumors enriching for interleukin-1 receptor-associated kinase 1 pathway activation (pair)

Conditions: Breast Cancer

Summary: this is a single arm, open-label, lead in phase ib dose confirmation, followed by phase ii study with 2 parallel study cohorts. patients will be pre-screened for presence of 1q21.3 copy number amplification in plasma samples prior to screening process. only patients with confirmed plasma cell-free dna (cfdna) 1q21.3 copy number amplification who successfully meet study eligibility criteria will be enrolled. the phase ib segment will be carried out in a standard 3+3 design, with a projected enrolment of 3 to 18 patients to determine the rp2d. in the phase ii portion, 2 parallel cohorts will be enrolled (cohort a: 1q21.3 amplified breast cancers, cohort b: 1q21.3 amplified other solid tumors). based on the simon 2 stage optimal design, 12 patients will be enrolled in each cohort for stage i of the study, and assessed for pfs. if at least 3 of 12 patients meet study response criteria, the study will then be expanded to stage 2 to include a total of 25 patients in each cohort. accounting for 10% attrition rate, a maximum of 28 patients will be enrolled into each cohort for phase ii of the study.

2.1. hypothesis * single agent pacritinib is effective in disease control of patients with 1q21.3 amplified solid tumors * single agent pacritinib is safe in patients with 1q21.3 amplified solid tumors * treatment with pacritinib will decrease plasma cfdna copy number ratio of 1q21.3 in patients with 1q21.3 amplified solid tumors * plasma cfdna copy number ratio of 1q21.3 will correlate with serial radiological findings in patients with 1q21.3 amplified solid tumors 2.2. primary objectives • to determine the proportion of patients with 1q21.3 amplified breast cancer (primary population: cohort a) who remain progression-free at 4 months after treatment with pacritinib 2.3. secondary objectives * to determine the safety and tolerability of pacritinib in patients with treatment refractory solid tumors * to determine the rp2d of pacritinib in patients with treatment refractory solid tumors * to evaluate disease response from pacritinib by recist criteria version 1.1 and tumor markers * to determine the proportion of patients with 1q21.3 amplified treatment refractory solid tumors excluding (exploratory population: cohort b) who remain progression-free at 4 months after treatment with pacritinib 2.4. exploratory objectives * to determine pharmacokinetic (pk) parameters including cmax/min and steady state concentrations of pacritinib through serial plasma sampling * to determine pharmacodynamics (pd) parameters including highly sensitive c-reactive protein (crp), hba1c, changes in cytokine levels and plasma cfdna levels of copy number ratio of 1q21.3 * correlation of plasma cfdna levels of copy number ratio of 1q21.3 with radiological findings determined by recist criteria 1.1 and tumor markers

Eligibility criteria:
inclusion criteria: patients may be included in the study only if they meet all of the following criteria: * age \> or = 21 years. * histological or cytological diagnosis of malignant advanced solid tumors refractory to standard therapy or for which no suitable effective standard therapy exists. o patients who fit above criteria will be pre-screened for presence of 1q21.3 amplification using a plasma assay based on digital pcr. patients with tumors that exhibit 1q21.3amplification will be enrolled. positive 1q21.3 amplification is defined as more than 3 standard deviations above the mean comparing the averaged copy number ratio of 3 genes (tuft1, s100a8 and s100a7) relative to the reference gene rpp30 measure in sample (13). * ecog 0-2 * has measureable or evaluable disease based on recist 1.1 criteria * estimated life expectancy of at least 12 weeks. * has documented progressive disease from last line of therapy * has recovered from acute toxicities from prior anti-cancer therapies * adequate organ function including the following: * bone marrow: * absolute neutrophil (segmented and bands) count (anc) \> or = 1.5 x 109/l * platelets \> or = 100 x 109/l * hemoglobin \> or = 8 x 109/l * hepatic: * bilirubin \< or = 1.5 x upper limit of normal (uln), * alt or ast \< or = 2.5x uln, (or \< or = 5 x with liver metastases) * renal: * creatinine \< or = 1.5x uln * signed informed consent from patient * able to comply with study-related procedures. * prior therapy (patients enrolled in phase ib may be enrolled if they fulfil prior therapy criteria for either cohort a or cohort b) * cohort a only: has received at least 2 lines of systemic therapy (endocrine or chemotherapy) in the palliative setting. chemotherapy in an adjuvant setting for which patients relapsed within 6 months of completion can be considered as line(s) of palliative therapy. * cohort b only: any number of prior lines of palliative chemotherapy. exclusion criteria: patients will be excluded from the study for any of the following reasons: * treatment within the last 30 days with any investigational drug. * concurrent administration of any other tumour therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy. * major surgery within 28 days of study drug administration. * active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy. * pregnancy. * breast feeding. * serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator. * significant recent bleeding history defined as ctcae grade 2 or higher within the past 3 months, unless precipitated by an inciting event (e.g. surgery, trauma, injury). * suboptimal cardiac function, defined by: * any history of ctcae grade \> or = 2 non-dysrhythmia cardiac conditions within the last 6 months * new york heart association class ii, iii or iv congestive cardiac failure * left ventricular ejection fraction of \<45% * qtc prolongation of \>450ms as assessed by ecg or other factors that increase the risk of qt interval prolongation * second primary malignancy that is clinically detectable at the time of consideration for study enrollment. * symptomatic brain metastasis. * history of significant neurological or mental disorder, including seizures or dementia. * unable to comply with study procedures * systemic treatment with a strong cyp3a4 inhibitor or storn cyp450 inducer within 14 days prior to treatment day 1 phase ib lead-in can recruit patients who fulfil critieria for either cohort a or cohort b and all other inclusion/exclusion criteria

Keywords: 1q21.3 interleukin-1 receptor-associated kinase 1 pacritinib irak1