Venetoclax, SL-401, and Chemotherapy for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm

Study Overview
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Brief Summary
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This phase II trial studies how well venetoclax, SL-401, and chemotherapy works in treating patients with blastic plasmacytoid dendritic cell neoplasm. Venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. SL-401 is a recombinant protein consisting of IL-3 linked to a toxic agent called DT. IL-3 attaches to IL-3 receptors on tumor cells in a targeted way and delivers DT to kill them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax and SL-401 with chemotherapy may be an effective treatment for patients with blastic plasmacytoid dendritic cell neoplasm.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate progression-free survival (PFS) at 12 months of venetoclax (VEN) in combination with chemotherapy and SL-401 (tagraxofusp [TAG]) in patients with newly diagnosed blastic plasmacytoid dendritic cell neoplasm (BPDCN). SECONDARY OBJECTIVES: I. To determine the safety of the SL-401 in combination with VEN and in combination with chemotherapy in patients with newly diagnosed BPDCN by toxicity and futility monitoring. II. To determine the efficacy by measurement of progression free survival (PFS), overall response rate (ORR): complete response (CR) and complete response with incomplete marrow recovery (CRi), clinical complete response (CRc) and remission duration of SL-401 in combination with chemotherapy and VEN in patients with newly diagnosed BPDCN. III. To determine the rate of stem cell translant (SCT) within the first 8 cycles (understanding that some patients won't get SCT) in patients with newly diagnosed BPDCN. EXPLORATORY OBJECTIVES: I. To examine expression and function of BCL-2 family proteins and its modulation by VEN in BPDCN blasts. II. To determine the rate of minimal residual disease (MRD) negativity in patients achieving CR/CRi/CRc and its correlation with disease-free survival (DFS) and overall survival (OS). III. To determine CD123 levels pre- and post-therapy. IV. To determine molecular mutations pre-and post- therapy as part of 81-gene panel by next-generation sequencing. OUTLINE: INDUCTION: CYCLE 1: Patients receive tagraxofusp-erzs (SL-401) intravenously (IV) once daily (QD) over 15 minutes on days 1-5. CYCLES 2, 4, 6, and 8: Patients receive tagraxofusp-erzs IV QD over 15 minutes on days 1-5, and venetoclax orally (PO) QD on days 1-14 of cycle 2, and days 1-7 of cycles 4, 6, and 8. CYCLES 3 and 7: Patients receive venetoclax PO QD on days 1-7. Patients whose age < 60 receive hyper-CVAD and age >= 60 receive mini-hyper-CVD. Patients may receive rituximab IV over 90 minutes on days 1 and 8, methotrexate intrathecally (IT) on day 2, and/or cytarabine IT on day 8. Patients also receive venetoclax PO QD on days 1-7. HYPER-CVAD (AGE < 60): Patients receive cyclophosphamide IV over 3 hours every 12 hours (Q12H) on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone orally (PO) or IV over 30 minutes on days 1-4 and 11-14, and doxorubicin IV over 24 hours on day 4. MINI-HYPER-CVD (AGE >= 60): Patients receive cyclophosphamide IV over 3 hour Q12H on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone PO or IV over 30 minutes on days 1-4 and 11-14. CYCLE 5: Patients receive venetoclax PO QD on days 1-7. Patients who age < 60 receive MTX/AraC and age >= 60 receive mini-MTX/AraC. Patients may receive rituximab IV over 4-6 hours on days 1 and 8, cytarabine IT on day 5, and/or methotrexate IT on day 8. MTX/ARAC (AGE < 60): Patients receive methotrexate IV over 24 hours on day 1, and cytarabine IV over 3 hours Q12H on days 2 and 3. MINI-MTX/ARAC (AGE >= 60): Patients receive methotrexate IV over 24 hours on day 1, methylprednisolone IV over 2 hours Q12H on days 1-3, and cytarabine IV over 3 hours Q12H on days 2 and 3. ALL CYCLES: Treatment repeats every 28 days for 8 cycles in the absence of disease progression and unacceptable toxicity. MAINTENANCE: Patients receive venetoclax PO QD on days 1-7, POMP chemotherapy during cycles 1-5, 7-11, and 13-17, and SL-401 IV QD on days 1-5 of cycles 6, 12, and 18. Treatment repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable toxicity. POMP: Patients receive mercaptopurine PO three time daily (TID) on days 1-28, vincristine IV over 15 minutes on day 1, prednisone PO QD on days 1-5, and methotrexate PO once weekly. After completion of study treatment, patients are followed up at 30 days, and then every 3 months thereafter.

Official Title
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Phase 2 Clinical Trial for Comprehensive Treatment Program for Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Tagraxofusp (SL-401) in Combination With HCVAD/Mini-CVD and VENETOCLAX

Conditions
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Blastic Plasmacytoid Dendritic Cell Neoplasm

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Methylprednisolone
* Drug: Prednisone
* Biological: Rituximab
* Biological: Tagraxofusp-erzs
* Drug: Venetoclax
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) per 2016 World Health Organization (WHO) criteria Patients may have received emergent chemotherapy prior to study enrollment: One prior cycle of SL-401, or other BPDCN-directed therapy, will be allowed prior to entering the study Prior or concomitant doses of aspacytarabine (ARA-C [cytarabine]) or hydroxyurea are allowed on before or during the study for proliferative disease due to BPDCN Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Albumin >= 3.2 g/dL (in the absence of receipt of intravenous albumin in the previous 72 hours) Serum creatinine < 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN Total bilirubin < 1.5 x ULN (if total bilirubin is > 1.5 x but < 3 x ULN, and thought to be elevated due to Gilbert's disease or the patient's BPDCN, the subject may be eligible but must discuss with the principal investigator [PI]). Ability to understand and the willingness to sign a written informed consent document Able to adhere to study visit schedule and other protocol requirements including follow-up for survival assessment Women of child-bearing potential and men enrolled on this protocol must agree to use adequate contraception for the duration of study participation and for 2 months after completion VEN administration. Acceptable birth control methods allowed to be used while on study include: Birth control pills or injections, intrauterine devices (IUDs), double-barrier methods for example condom in combination with spermicide. Males should not donate sperm while on study and for at least 8 weeks after the last dose of SL-401 Left ventricular ejection fraction >= institutional lower limit of normal by multi-gated acquisition (MUGA) scan or echocardiogram within 30 days of first protocol treatment Exclusion Criteria: Patient is pregnant or breastfeeding Known active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV) Major surgery or radiation therapy within 14 days prior to the first study dose Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and/or dexamethasone, or one dose of cytarabine) prior to starting therapy Symptomatic or untreated leptomeningeal disease or spinal cord compression Patients with active heart disease (New York Heart Association [NYHA] class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months) Prior treatment with VEN Malabsorption syndrome or other conditions that preclude enteral route of administration Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (SL-401, venetoclax, chemotherapy)<br>See detailed description. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IT or IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT, IV, or PO<br>* Other names: WR-19039;Drug: Methylprednisolone<br>* Given IV<br>* Other names: Wyacort;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;Biological: Tagraxofusp-erzs<br>* Given IV<br>* Other names: Tagraxofusp ERZS;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | The median PFS time will be estimated by Bayesian posterior estimates. Estimated using the Kaplan-Meier method. | Up to 6 years | 
| Incidence of adverse events | Will be reported by type, frequency and severity. Highest toxicity grades per patient per course will be tabulated for selected adverse events and laboratory measurements. | Up to 6 years | 
| Overall response rate | Overall response rate along with complete remission and complete remission with incomplete hematologic recovery will be estimated along with 95% confidence interval. | Up to 6 years | 
| Rate of stem cell transplant | The response rate will be compared between subgroups (e.g. minimal residual disease negativity, etc.) by Fisher's exact test, and Wilcoxon rank test will be used to compare the patient clinical information (e.g., protein expression) between subgroups such as response and non-response. | Up to 6 years |