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Tagraxofusp-erzs

Nicholas Short, MD

Nicholas Short

This phase Ib/II trial studies the effects of tagraxofusp and low-intensity chemotherapy in treating patients with CD123 positive acute lymphoblastic leukemia or lymphoblastic lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Tagraxofusp consists of human interleukin 3 (IL3) linked to a toxic agent called DT388. IL3 attaches to IL3 receptor positive cancer cells in a targeted way and delivers DT388 to kill them. Chemotherapy drugs, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tagraxofusp with chemotherapy may help control CD123 positive relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma.

PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (complete response \[CR\] + CR with inadequate count recovery \[CRi\]) of the regimen within 3 cycles.

SECONDARY OBJECTIVES:

I. Evaluate other clinical efficacy endpoints (CR rate, minimal residual disease \[MRD\] negativity, duration of response \[DOR\], relapse-free survival \[RFS\] overall survival \[OS\]).

II. Determine the proportion of patients proceeding to allogeneic stem cell transplantation (allo-SCT).

III. Determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To determine CD123 expression levels pre- and post-therapy. II. To correlate baseline CD123 expression with response rates and duration of response.

III. To evaluate change in apoptotic protein expression and alterations in cellular signaling pathways using cytometry by time of flight (CyTOF).

IV. To determine baseline gene expression profile in order to identify ALL subtypes and correlate with clinical outcomes and response to single-agent tagraxofusp-erzs (tagraxofusp).

OUTLINE:

TAGRAXOFUSP AND CHEMOTHERAPY PHASE:

CYCLE 1: Patients receive tagraxofusp-erzs intravenously (IV) over 15 minutes on days 1-5.

CYCLES 2 AND 4: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-3, cyclophosphamide IV over 3 hours twice daily (BID) and mesna IV on days 4-6, vincristine IV over 15 minutes on days 4 and 15, dexamethasone IV over 30 minutes or orally (PO) on day 4-7 and 14-17, methotrexate intrathecally (IT) on day 5, and filgrastim-sndz subcutaneously (SC) or pegfilgrastim SC on day 8, and cytarabine IT on day 10. Patients may receive rituximab IV over 4-6 hours on days 4 and 14.

CYCLES 3 AND 5: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-3, methotrexate IV over 24 hours on day 4, cytarabine IV over 3 hours BID on days 5-6, filgrastim-sndz SC or pegfilgrastim SC on day 6, methotrexate IT and cytarabine IT on day 11. Patients may receive rituximab IV over 4-6 hours on days 4 and 11. Beginning about 12 hours after the day 4 dose of methotrexate, patients may also receive leucovorin IV over 15 minutes, 4 times a day for about 8 doses.

CYCLES 6 AND 8: Patients receive cyclophosphamide IV over 3 hours BID and mesna IV on days 1-3, vincristine IV over 15 minutes on days 1 and 11, dexamethasone IV over 30 minutes or PO on day 1-4 and 11-14, and filgrastim-sndz SC or pegfilgrastim SC on day 5.

CYCLES 7 AND 9: Patients receive methotrexate IV over 24 hours on day 1, cytarabine IV over 3 hours BID on days 2-3, and filgrastim-sndz SC or pegfilgrastim SC on day 4. Beginning about 12 hours after the day 1 dose of methotrexate, patients may receive leucovorin IV over 15 minutes, 4 times a day for about 8 doses.

Cycle 1 is 21 days. Treatment repeats every 28 days for cycles 2-9 in the absence of disease progression or unacceptable toxicity.

TAGRAXOFUSP AND MAINTENANCE PHASE:

CYCLES 1-3, 5-7, 9-11, 13-15: Patients receive mercaptopurine PO three time daily (TID) on days 1-28, prednisone PO once daily (QD) on day 1-5, methotrexate PO once every week (QW) and vincristine IV over 15 minutes every 4 weeks.

CYCLES 4, 8, and 12: Patients receive tagraxofusp-erzs IV over 15 minutes on days 1-5.

Treatment repeats every 28 days for 15 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Tagraxofusp and Low-Intensity Chemotherapy for the Treatment of CD123 Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Phase Ib/II Study of the Combination of Low-Intensity Chemotherapy and Tagraxofusp in Patients With Acute Lymphoblastic Leukemia (ALL)

Will be monitored simultaneously using the Bayesian approach. Will be estimated along with 95% credible intervals. Chi-square tests or Fisher's exact test will be used to evaluate the association between patient's prognostic factor and response.

Will be estimated along with 95% credible intervals. Chi-square tests or Fisher's exact test will be used to evaluate the association between patient's prognostic factor and response.

Kaplan-Meier method will be used to estimate the RFS.

Kaplan-Meier method will be used to estimate the overall survival.

M.D. Anderson Cancer Center

Infections

Lymphoma, B-Cell

Burkitt Lymphoma

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Etoposide

Bortezomib

Etoposide phosphate

Podophyllotoxin

Ofatumumab

Clofarabine

Keratolytic Agents

Vincristine Sulfate Liposome

Maro Ohanian

This phase II trial studies the side effects and how well combination chemotherapy works in treating patients with acute lymphoblastic leukemia, lymphoblastic lymphoma, Burkitt lymphoma/leukemia, or double-hit lymphoma/leukemia that has come back or does not respond to treatment. Drugs used in chemotherapy, such as clofarabine, etoposide, cyclophosphamide, vincristine sulfate liposome, dexamethasone and bortezomib, 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.

PRIMARY OBJECTIVE:

I. To collect the safety/toxicity information and assess the initial efficacy information (objective overall response rate: complete response \[CR\]+ CR with incomplete platelet recovery \[CRp\]/CR with incomplete bone marrow recovery \[CRi\]) after treatment with clofarabine, etoposide, cyclophosphamide (CEC), vincristine sulfate liposome (liposomal vincristine) (VCR), dexamethasone and bortezomib in relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) including relapsed/refractory Philadelphia (Ph) positive B-ALL/LL or Burkitt's leukemia/lymphoma or double-hit leukemia/lymphoma.

SECONDARY OBJECTIVE:

I. To determine the CR duration, event free survival (EFS), and overall survival (OS) after treatment with CEC, liposomal VCR, dexamethasone and bortezomib in relapsed/refractory ALL or LL including relapsed/refractory Ph positive B-ALL/LL or Burkitt's leukemia/lymphoma or double-hit leukemia/lymphoma.

OUTLINE:

INDUCTION: Patients receive clofarabine intravenously (IV) over 1-2 hours on days 1-5, etoposide IV over 2 hours on days 1-5, cyclophosphamide IV over 1 hour on days 1-5, vincristine sulfate liposome IV over 1 hour on days 2 and 11, dexamethasone orally (PO) daily or IV over 15 minutes on days 1-5, bortezomib subcutaneously (SC) on days 1, 4, 8 and 11, ofatumumab or rituximab IV over 4-24 hours on days 2 and 11, and pegfilgrastim SC on day 6 in the absence of disease progression or unacceptable toxicity. Patients may receive 1 additional course of induction therapy depending on the disease response.

CONSOLIDATION THERAPY: Patients receive clofarabine IV over 1-2 hours on days 1-4, etoposide IV over 2 hours on days 1-4, cyclophosphamide IV over 1 hour on days 1-4, vincristine sulfate liposome IV over 1 hour on days 2 and 11, dexamethasone PO or IV over 15 minutes on days 1-5, bortezomib SC on days 1, 4, 8 and 11, pegfilgrastim SC on day 6. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients may receive ofatumumab or rituximab IV over 4-24 hours on days 2 and 11 for 4 courses.

Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma, Burkitt Lymphoma/Leukemia, or Double-Hit Lymphoma/Leukemia

Lead-In and Phase II Study of Clofarabine, Etoposide, Cyclophosphamide [CEC], Liposomal Vincristine (VCR), Dexamethasone and Bortezomib in Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL)

The severity of the toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events.

Will be estimated along with the exact 95% confidence interval.

Will be estimated using the method of Kaplan and Meier. The log-rank tests will be used to compare the time-to-event outcomes among subgroups of patients.

National Cancer Institute (NCI)

Sirolimus

Temsirolimus

MTOR Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Adding sirolimus to established induction and consolidation chemotherapy for relapsed/refractory acute lymphoblastic leuk

Adding sirolimus to established induction and consolidation chemotherapy for relapsed/refractory acute lymphoblastic leukemia

Maureen O'Brien, MD

The investigators want to learn about treating relapsed/refractory lymphoblastic leukemia and lymphoma with a drug called sirolimus. The investigators are using sirolimus along with other cancer drugs that are often given to patients with relapsed leukemia and lymphoma.

The main purpose of this study is to determine if sirolimus can be given safely in combination with standard drugs used to treat relapsed lymphoblastic leukemia/lymphoma.

You will receive the drug sirolimus in addition to standard chemotherapy drugs.

Just like your original cancer treatment, relapsed leukemia/lymphoma treatment is divided into different parts. You will get sirolimus during the first two parts:

1. Re-induction: We give chemotherapy drugs to try to put your cancer back into remission, meaning that no cancer cells are found in the bone marrow samples (if you have leukemia) or on imaging studies (if you have lymphoma). From start to finish, this part of therapy lasts 35 days. On this study, you will take the drug sirolimus daily in addition to the normal re-induction chemotherapy drugs. You will swallow liquid sirolimus and you must take it with food. You will take sirolimus three times on the first day and two times each day after that during re-induction.

   Altogether, this is the schedule for re-induction:
   * Sirolimus by mouth starting 7 days before standard re-induction starts, and continuing every day through day 28
   * Mitoxantrone by vein on days 1 and 2
   * Vincristine by vein on days 3, 10, 17 and 24
   * Dexamethasone by vein or by mouth on days 1-5 and 15-19
   * PEG-asparaginase\* on days 3 and 17
   * IT Methotrexate given in spinal fluid on day 1 (all patients) day 8,29 (if no cancer found in spinal fluid)
   * IT Triples given in spinal fluid on days 8,15,22,29 (if cancer found in spinal fluid)

   (If you have an allergic reaction to PEG-asparaginase, you may be given 6 doses of Erwinia L-asparaginase instead)
2. Consolidation: We give drugs to continue to kill cancer cells in your body and prevent them from coming back. From start to finish, this part of therapy will last 63 days (it could be longer if we have to interrupt your treatment because you have low blood counts, and you need to wait for them to come up). On this study, you will take the drug sirolimus daily in addition to the normal consolidation chemotherapy drugs. You will take sirolimus three times on the first day and two times each day after that during consolidation.

   Altogether, this is the schedule for consolidation:
   * Sirolimus by mouth starting 7 days before consolidation starts, and continuing every day through day 56.
   * Cyclophosphamide by vein on days 1 and 29
   * Cytarabine by vein or under skin on days 1-4, 8-11, 29-32, 36-39
   * 6-mercaptopurine by mouth on days 1-14, 29-42
   * PEG-asparaginase\* by vein on days 15 and 43
   * Vincristine by vein on days 15 and 43
   * It Methotrexate in spinal fluid on Days 1 and 29
3. After you complete re-induction and consolidation, your doctor will determine the next steps of your treatment. This will depend on how you are doing and it will be up to you and your doctor. It will not be part of this study.

This research only includes the re-induction and consolidation portions of treatment (1 and 2, above). If you have already done re-induction, you can enter the study for consolidation only.

In addition to all the regular tests and procedures done to check on your cancer during this study, we will also take additional blood samples to monitor the levels of sirolimus in your blood (in order to adjust your dose) and we will also take blood samples to find certain markers in your blood that might indicate that the sirolimus is doing what it is supposed to do.

Pilot Study Of Sirolimus Plus Multiagent Chemotherapy For Relapsed/Refractory Acute Lymphoblastic Leukemia/Lymphoma

The safety of the regimen will be assessed by the occurrence of unexpected or severe adverse events attributable to sirolimus

MAST (maximum acceptable sirolimus trough) will be the serum trough range at which fewer than one third of patients experience dose limiting toxicities during the observation period (28 days)

Disease response will be assessed according to standard criteria

Peripheral blood samples (5mL) will be obtained at day -6 (baseline), 1, 3,8, 29 of induction and day -6 (baseline), 1, 8, 29, 36 of consolidation for measurement of pAKT, p-S6, p70S6 kinase activity, and single-cell phosphoflow studies in peripheral blood mononuclear cells

Use serial measurements of sirolmus trough levels and PK modeling to adjust individual patient sirolimus dose.

Children's Hospital Medical Center, Cincinnati

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tagraxofusp and Low-Intensity Chemotherapy for the Treatment of CD123 Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma	NCT05032183	Recurrent Adult... Recurrent B Acu... Recurrent T Acu... Refractory B Ac... Refractory Lymp... Refractory T Ac...	Cyclophosphamid... Cytarabine Dexamethasone Filgrastim-sndz Leucovorin Mercaptopurine Mesna Methotrexate Pegfilgrastim Prednisone Rituximab Tagraxofusp-erz... Vincristine	18 Years - 70 Years	M.D. Anderson Cancer Center
Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma, Burkitt Lymphoma/Leukemia, or Double-Hit Lymphoma/Leukemia	NCT03136146	Recurrent Acute... Recurrent Adult... Recurrent Burki... Recurrent Burki... Recurrent Child... Recurrent High ... Refractory Acut... Refractory Burk... Refractory Burk... Refractory High... Refractory Lymp...	Bortezomib Clofarabine Cyclophosphamid... Dexamethasone Etoposide Ofatumumab Pegfilgrastim Rituximab Vincristine Sul...	15 Years -	M.D. Anderson Cancer Center
Pilot Study Of Sirolimus Plus Multiagent Chemotherapy For Relapsed/Refractory Acute Lymphoblastic Leukemia/Lymphoma	NCT01658007	Relapsed Lympho... Recurrent Adult... Refractory Acut... Refractory Lymp...	Sirolimus	- 30 Years	Children's Hospital Medical Center, Cincinnati

Spots Global Cancer Trial Database for refractory lymphoblastic lymphoma