Subcutaneous Blinatumomab Plus Ponatinib for BCR-ABL+ B-ALL

This Phase II clinical trial will evaluate with efficacy and tolerance of subcutaneous (sc) blinatumomab (blina) combined with ponatinib for previously untreated patients with BCR-ABL (Ph) positive B-cell acute lymphoblastic leukemia (ALL).

Participants will, after a brief steroid pre-phase, receive induction therapy with ponatinib 30 mg/day x 70 days, with prednisone for the first month. They will then receive 5 cycles of consolidation therapy with sc blina. The first cycle will consist of blina 250 mcg sc daily x 7 days, then 500 mcg sc 3x/week x 3 weeks. Cycles 2-5 will consist of blina 500 mcg sc 3x/week x 4 weeks. There will be a 2 week break in between each consolidation cycle. Ponatinib will continue at 30 mg daily through the end of consolidation. Participants will then receive maintenance therapy with ponatinib 15 mg/day until 5 years from the start of induction.

Intrathecal chemotherapy will be administered for a total of 15 doses; this will include 7 doses during induction, 1 dose in between each consolidation cycle, and 4 during maintenance.

Efficacy will be determined by bone marrow assessments for MRD at various timepoints. The primary endpoint is the measurable residual disease (MRD) response after the end of consolidation cycle 2, by both BCR-ABL PCR (MRD4 or greater) and by IgR (MRD negativity by Clonoseq[R]). The CR rate, MRD response duration, RFS and OS will also be assessed.

Toxicity will be evaluated throughout the study and graded using CTCAE V5. Quality of life will be assessed at various timepoints using QLQ-C30.

Inclusion criteria

• Ph positive [either t(9;22) and/or BCR-ABL1 positive] ALL, CD19 positive
• Age ≥18 years at time of informed consent
• No prior induction treatment for ALL. A brief corticosteroid pre-phase (< 1 week), or hydroxyurea for cytoreduction or symptom control is permitted.

• Greater than or equal to 5% blasts in the BM.

• Performance status ≤2 (ECOG Scale, see Appendix IV)

• Adequate organ function: 5.1.5.1 Hepatic:

Adequate liver function as defined by the following criteria (unless the increased values are judged to be leukemia disease related):

Total serum bilirubin less than 2 x upper limit of normal (ULN), unless due to Gilbert's syndrome or Meulengracht disease Alanine aminotransferase (ALT) less than 3 x ULN Aspartate aminotransferase (AST) less than 3 x ULN 5.1.5.2 Pancreatic:

• Serum lipase less than 2 x ULN 5.1.5.3 Renal:
• Estimated Creatinine clearance ≥ 40 mL/min 5.1.5.4 Cardiac:
• Left ventricular ejection fraction > 40%

Exclusion criteria

• Uncontrolled infection
• Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus
• Presence of cardiovascular disease of clinical relevance within the past 3 months. This includes:

5.2.3.1 Unstable angina 5.2.3.2 Myocardial infarction 5.2.3.3 Transient ischemic attack or stroke 5.2.3.4 Peripheral vascular infarction, claudication and/or revascularization 5.2.3.5 Symptomatic congestive heart failure 5.2.3.6 Clinically significant significant atrial/ventricular tachyarrhythmias 5.2.3.7 Venous thromboembolic event requiring systemic anticoagulation

Please consult the sponsor if there are specific concerns outside of these criteria

• Uncontrolled hypertension
• History or presence of clinically relevant CNS pathology or event.

This may include, for example:

epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome or psychosis.

Before excluding a potential subject, please consult the sponsor.

• Any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol.
• History of malignancy other than ALL within 3 years prior to start of protocol-specified therapy except for:

• malignancy treated with curative intent and with no known active disease present for 3 years before enrollment, and felt to be at low risk for recurrence by the treating physician
• adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• adequately treated cervical carcinoma in situ without evidence of disease
• adequately treated breast ductal carcinoma in situ without evidence of disease
• prostatic intraepithelial neoplasia without evidence of prostate cancer
• Prior hematologic malignancy and/or alloSCT; this includes known CML
• Concurrent or prior (within 30 days) treatment with another investigational agent or study drug
• Female subject is pregnant or breastfeeding or planning to become pregnant breastfeed during treatment, and for an additional 4 months after the last dose of protocol-specified therapy
• Inability to swallow or absorb tablets
• Subject considered unsuitable for study for any other reason in the physician's best judgement. Before excluding a potential subject, please consult the sponsor.