Venetoclax + Tagraxofusp-erzs + Chemotherapy for BPDCN

Overseen By Naveen Pemmaraju, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnancy, Hepatitis B/C, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 30

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs, including venetoclax, tagraxofusp-erzs (also known as SL-401), and chemotherapy, to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare cancer. The goal is to determine if these drugs can halt cancer cell growth by blocking key enzymes and delivering a toxin directly to the cancer cells. Individuals with BPDCN, whether previously treated or newly diagnosed with specific cancer types, might be eligible to participate. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it allows for certain medications like ARA-C (cytarabine) or Hydroxyurea to be used before or during the study for specific conditions related to BPDCN.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that venetoclax and tagraxofusp-erzs are generally safe for people. Tagraxofusp-erzs is specifically approved for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). It is considered safe and manageable, though there is a risk of capillary leak syndrome (CLS), where fluid leaks from small blood vessels. Proper care can usually manage this condition.

Venetoclax blocks proteins that help cancer cells grow. Its safety is well-known due to its use in other conditions. The treatment also includes chemotherapy drugs like cyclophosphamide and cytarabine. These drugs are well-researched but can cause common side effects such as nausea and tiredness. Overall, studies suggest that the combination of these treatments in trials is generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Venetoclax, Tagraxofusp-erzs, and chemotherapy for treating BPDCN because it brings a novel approach to tackling this rare cancer. Unlike standard treatments like chemotherapy alone or stem cell transplants, which mainly target rapidly dividing cells, Venetoclax specifically inhibits a protein called BCL-2. This protein helps cancer cells survive, so targeting it can make cancer cells more vulnerable to treatment. Additionally, Tagraxofusp-erzs is a targeted therapy that specifically attacks cells expressing the CD123 protein, commonly found in BPDCN. This dual-targeted strategy not only aims to directly kill cancer cells but also reduces the chance of harming healthy cells, potentially leading to more effective and less toxic treatment outcomes.

What evidence suggests that this trial's treatments could be effective for BPDCN?

In this trial, participants will receive a combination of venetoclax, Tagraxofusp-erzs, and chemotherapy. Studies have shown that venetoclax, a drug that inhibits proteins aiding cancer cell survival, shows promise for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). When combined with other treatments, it has improved survival rates. Tagraxofusp-erzs, a targeted therapy approved for BPDCN, delivers a toxin to cancer cells, resulting in strong and lasting responses. This drug targets a specific protein on BPDCN cells and has demonstrated strong antitumor activity in various studies. Both treatments have shown encouraging results, making them potential options for those with BPDCN. ^{6 7 8 9 10}

Who Is on the Research Team?

Naveen Pemmaraju, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with a confirmed diagnosis of blastic plasmacytoid dendritic cell neoplasm. Participants should be in relatively good health (ECOG status 0-2), have normal heart function, and agree to use effective contraception. People who've had major surgery or certain treatments recently, are pregnant or breastfeeding, have active hepatitis B/C or HIV, severe heart issues, malabsorption syndrome, untreated brain/spinal cord problems, or prior venetoclax treatment can't join.

Inclusion Criteria

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])

I have taken or am taking ARA-C or hydroxyurea for BPDCN.

Exclusion Criteria

I have previously been treated with VEN.

I haven't had chemotherapy, radiotherapy, or experimental treatments in the last 14 days, except for specific allowed medications.

Patient is pregnant or breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive tagraxofusp-erzs (SL-401) and venetoclax with chemotherapy over multiple cycles

8 cycles (28 days each)

Multiple visits per cycle for drug administration

Maintenance

Patients receive venetoclax and POMP chemotherapy over 24 cycles

24 cycles (28 days each)

Regular visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

Follow-up at 30 days, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Cytarabine
• Dexamethasone
• Doxorubicin
• Mercaptopurine
• Methotrexate
• Methylprednisolone
• Prednisone
• Rituximab
• Tagraxofusp-erzs
• Venetoclax
• Vincristine

Trial Overview The study tests the effectiveness of combining venetoclax and SL-401 with standard chemotherapy in treating blastic plasmacytoid dendritic cell neoplasm. Venetoclax targets enzymes needed for tumor growth; SL-401 delivers a toxin directly to tumor cells via IL-3 receptors; chemotherapy aims to kill or stop cancer cells from growing and spreading.

How Is the Trial Designed?

Group I: Treatment (SL-401, venetoclax, chemotherapy) Experimental Treatment 12 Interventions

See detailed description.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The CyclOBEAP regimen, which adds etoposide and bleomycin to a standard CHOP-like treatment, achieved an 88% complete response rate in 121 patients with aggressive lymphoma over a 12-week period, indicating its efficacy.

The 5-year overall survival rate was 72% and the progression-free survival rate was 62%, with no treatment-related deaths reported, suggesting that the regimen is safe while enhancing the effectiveness of traditional CHOP therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II study of the CyclOBEAP (CHOP-like + etoposide and bleomycin) regimen for patients with poor-prognosis aggressive lymphoma. Niitsu, N., Okamoto, M., Aoki, S., et al.[2015]

Cardioxan (dexrazoxan) was administered to 37 pediatric patients with various types of leukemia and lymphoma undergoing chemotherapy, specifically those receiving anthracycline antibiotics.

The treatment showed no adverse side effects and did not interfere with the effectiveness of the chemotherapy, indicating it is safe for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cardioxane in pediatric oncohematology]. Kurmashov, VI., Gavrilova, IE., Maiakova, SA., et al.[2013]

The bisdioxopiperazine compound (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane (ICRF 187) effectively reduces the cardiotoxic effects of doxorubicin in various mammalian species, suggesting a potential protective role during cancer treatment.

When combined with doxorubicin, the bisdioxopiperazine enhances the drug's antitumor effects, showing additive cytotoxicity at short exposure and synergistic effects with prolonged exposure, indicating that the timing and dosage of administration are crucial for maximizing therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic activity of doxorubicin and the bisdioxopiperazine (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF 187) against the murine sarcoma S180 cell line. Wadler, S., Green, MD., Muggia, FM.[2013]

In a study of 205 children with high-risk acute lymphoblastic leukemia (ALL), dexrazoxane did not increase the risk of developing secondary malignant neoplasms (SMNs) compared to those who received doxorubicin alone, with a median follow-up of 6.2 years.

The results support the continued use of dexrazoxane as a cardioprotectant during doxorubicin treatment in pediatric patients, as no SMNs were observed in the dexrazoxane group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. Barry, EV., Vrooman, LM., Dahlberg, SE., et al.[2022]

In a late phase II study involving 27 patients with non-Hodgkin's lymphoma, MST-16 demonstrated clinical efficacy with one complete remission and seven partial remissions, indicating its potential as a treatment option.

MST-16 showed significant toxicity, with 70% of patients experiencing leukopenia and 44% experiencing thrombocytopenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study: treatment of non-Hodgkin's lymphoma with an oral antitumor derivative of bis(2,6-dioxopiperazine). Ohno, R., Yamada, K., Hirano, M., et al.[2019]

In a study of 35 elderly patients with aggressive non-Hodgkin's lymphoma, the use of liposomal Daunorubicin (DNX) resulted in a high overall response rate of 77%, with 15 patients achieving complete remission (CR) and 5 achieving partial remission (PR).

Liposomal DNX demonstrated similar efficacy to traditional Daunorubicin while significantly reducing acute toxicity, making it a safer option for treating this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of liposomal daunorubicin included in PVABEC regimen for aggressive NHL of the elderly. Cervetti, G., Caracciolo, F., Cecconi, N., et al.[2019]

In a study of 42 children with newly diagnosed stage III or IV neuroblastoma, the OPEC chemotherapy regimen resulted in a good partial response in 74% of patients, with an even higher response rate of 78% among those who strictly followed the treatment protocol.

The OPEC regimen was found to be at least as effective as the more toxic OPEC-D regimen, with significantly lower treatment-related complications, suggesting it could be a safer alternative for treating advanced neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. Shafford, EA., Rogers, DW., Pritchard, J.[2017]

The hyper-CVAD regimen, which includes cyclophosphamide, vincristine, doxorubicin, and dexamethasone, has shown significant effectiveness in treating adult lymphocytic leukemia and other blood cancers, such as Burkitt's disease and multiple myeloma.

Clinical trials conducted at the University of Texas M. D. Anderson Cancer Center have provided strong evidence for the efficacy of hyper-CVAD, leading to ongoing discussions about strategies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The hyper-CVAD regimen in adult acute lymphocytic leukemia. Garcia-Manero, G., Kantarjian, HM.[2019]

Dexrazoxane effectively prevents heart damage caused by anthracycline chemotherapy without compromising its cancer-fighting ability or introducing new side effects.

In patients with advanced breast cancer, dexrazoxane not only alleviates gastrointestinal symptoms associated with chemotherapy but also significantly doubles the median survival time to nearly 3 years compared to those not receiving dexrazoxane.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview and historical development of dexrazoxane. Hellmann, K.[2013]

The OEPA-COPDAC chemotherapy regimen, which replaces procarbazine with etoposide and dacarbazine, was found to be tolerable in terms of toxicity for boys with Hodgkin's lymphoma, with hematotoxicity being less pronounced compared to the traditional COPP regimen.

After a median follow-up of 58.6 months, the overall survival rate was 97.4% and the event-free survival rate was 89.0%, indicating that OEPA-COPDAC is as effective as the standard OPPA-COPP regimen for treating intermediate and advanced stages of classical Hodgkin's lymphoma in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. Mauz-Körholz, C., Hasenclever, D., Dörffel, W., et al.[2022]

Anthracyclines like daunorubicin (DNR), rubidazone (RBD), and adriamycin (ADR) are effective chemotherapy drugs that work by inhibiting DNA and RNA synthesis and have shown significant antitumor activity in various cancers, including acute myeloid leukemia (AML) and solid tumors.

While these drugs are effective, they carry a risk of cardiac toxicity, particularly congestive heart failure, which limits their cumulative dosage; ongoing research is focused on developing new derivatives with similar efficacy but reduced cardiotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Survey of anthracyclines derivatives in haematology (author's transl)]. Jacquillat, C., Weil, M., Auclerc, MF., et al.[2013]

In a study involving 553 children with high-risk acute lymphoblastic leukemia (ALL) treated with dexrazoxane, the incidence of secondary malignant neoplasms (SMNs) was very low, with only one case of acute myelogenous leukemia (AML) reported over a median follow-up of 9.6 years.

The overall 5-year cumulative incidence of SMNs in these patients was just 0.24%, suggesting that dexrazoxane is a safe option for reducing anthracycline-related cardiotoxicity without significantly increasing the risk of developing secondary cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Vrooman, LM., Neuberg, DS., Stevenson, KE., et al.[2022]

A new regimen combining doxorubicin and paclitaxel has been developed that is both well-tolerated and highly effective, utilizing bolus administration of doxorubicin and a 3-hour infusion of paclitaxel, overcoming previous schedule-dependent toxicity issues.

Paclitaxel has shown promising results when combined with fluorouracil and folinic acid in patients with extensive prior chemotherapy, and adding mitoxantrone to this combination appears to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-based combination chemotherapy for breast cancer. Hortobagyi, GN.[2015]

In a study of 307 advanced-stage patients treated with the MOPPEBVCAD chemotherapy regimen, 94% achieved complete remission, demonstrating high efficacy in treating Hodgkin's lymphoma.

With a median follow-up of 114 months, the 10-year survival rates were 79% overall and 84% disease-free, while the incidence of second tumors was lower than expected, indicating a favorable safety profile compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MOPPEBVCAD chemotherapy with limited and conditioned radiotherapy in advanced Hodgkin's lymphoma: 10-year results, late toxicity, and second tumors. Gobbi, PG., Broglia, C., Levis, A., et al.[2015]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa1815105

Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell ... Tagraxofusp has shown potent antitumor activity against BPDCN cells in both in vitro and in vivo models, with cytotoxicity at femtomolar concentrations.

2. elzonris.com elzonris.com/hcp/long-term-efficacy

BPDCN Long-Term Efficacy - elzonris Long-term safety and efficacy of ELZONRIS, the first and only targeted FDA-approved treatment for BPDCN, were evaluated in the long-term analysis.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.00034

Long-Term Benefits of Tagraxofusp for Patients With Blastic ... In first-line patients with BPDCN, TAG monotherapy resulted in high and durable responses, allowing many to bridge to stem-cell transplant.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32841341/

Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic ... Tagraxofusp-erzs was the first agent approved for BPDCN (for patients ages 2 years and older), and importantly, established this drug as the first CD123- ...

5. haematologica.org haematologica.org/article/view/haematol.2022.282171

Tagraxofusp for blastic plasmacytoid dendritic cell neoplasm Here, we review the development of tagraxofusp, and the key preclinical insights and clinical data that led to approval. Tagraxofusp treatment ...

6. ashpublications.org ashpublications.org/bloodadvances/article/4/16/4020/463447/Approval-of-tagraxofusp-erzs-for-blastic

Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic ... Despite the signal for CLS, the drug was found to be quite safe and manageable, and was felt to be a possible breakthrough for patients with the ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04216524

Study Details | NCT04216524 | Venetoclax, SL-401, and ... This phase II trial studies how well venetoclax, SL-401, and chemotherapy works in treating patients with blastic plasmacytoid dendritic cell neoplasm.

8. jadpro.com jadpro.com/media/pjije0ju/care-optimization-for-patients-with-blastic-plasmacytoid-dendritic-cell-neoplasm-receiving-tagraxofusp.pdf

care-optimization-for-patients-with-blastic-plasmacytoid- ... Blastic plasmacytoid dendritic cell neoplasm is associated with a poor prognosis, and incidence is higher among males and patients aged ≥ 60.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7448601/

Approval of tagraxofusp-erzs for blastic plasmacytoid ... Despite the signal for CLS, the drug was found to be quite safe and manageable, and was felt to be a possible breakthrough for patients with the ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S2213048925000433

Real-world management of blastic plasmacytoid dendritic ... The development of tagraxofusp, a CD123-directed cytotoxin, has revolutionized BPDCN treatment, especially for patients unfit for chemotherapy. While most ...