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)

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