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)

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 tostandard therapy or for which no suitable effective standard therapy exists. o Patients who fit above criteria will be pre-screened for presence of 1q21.3amplification using a plasma assay based on digital PCR. Patients with tumors thatexhibit 1q21.3amplification will be enrolled. Positive 1q21.3 amplification is definedas more than 3 standard deviations above the mean comparing the averaged copy numberratio of 3 genes (TUFT1, S100A8 and S100A7) relative to the reference gene RPP30measure 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 priortherapy criteria for either Cohort A or Cohort B)

• Cohort A only: Has received at least 2 lines of systemic therapy (endocrine orchemotherapy) in the palliative setting. Chemotherapy in an adjuvant setting forwhich patients relapsed within 6 months of completion can be considered asline(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 cytotoxicchemotherapy, hormonal therapy, and immunotherapy.

• Major surgery within 28 days of study drug administration.

• Active infection that in the opinion of the investigator would compromise thepatient's ability to tolerate therapy.

• Pregnancy.

• Breast feeding.

• Serious concomitant disorders that would compromise the safety of the patient orcompromise the patient's ability to complete the study, at the discretion of theinvestigator.

• 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 thelast 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 riskof QT interval prolongation

• Second primary malignancy that is clinically detectable at the time of considerationfor study enrollment.

• Symptomatic brain metastasis.

• History of significant neurological or mental disorder, including seizures ordementia.

• Unable to comply with study procedures

• Systemic treatment with a strong CYP3A4 inhibitor or storn CYP450 inducer within 14days prior to treatment Day 1 Phase Ib lead-in can recruit patients who fulfil critieria for either Cohort A or Cohort BAND all other inclusion/exclusion criteria