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)

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