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Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing.

Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations

Chemosensitivity Assay

Cytology Specimen Collection Procedure

Analysis of leukemia cell genes to identify possible drug targets

Gene Expression Analysis

Genetic Variation Analysis

Receive personalized chemotherapy with one or more of the following drugs:

Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin

In Vitro Sensitivity-Directed Chemotherapy

Mary-Elizabeth Percival

This pilot clinical trial studies the feasibility of choosing treatment based on a high throughput ex vivo drug sensitivity assay in combination with mutation analysis for patients with acute leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). A high throughput screening assay tests many different drugs individually or in combination that kill leukemia cells in tiny chambers at the same time. High throughput drug sensitivity assay and mutation analysis may help guide the choice most effective for an individual's acute leukemia.

PRIMARY OBJECTIVES:

I. To test patient cells in a high throughput assay against individual drugs and drug combinations within 21 days to enable optimal choice of drug combinations for therapy.

II. To test gene expression that reveals activation of druggable pathways or mutations in genes that confer susceptibility to specific agents may also be considered in choice of treatment.

SECONDARY OBJECTIVE:

I. To evaluate the response to the chosen therapy.

OUTLINE:

Leukemia cells obtained from blood or bone marrow are analyzed for sensitivity to both individual drugs and drug combinations via high throughput chemotherapy sensitivity assay and next generation sequencing assays. Doctors will then recommend chemotherapy regimens based on the results.

After completion of the chemotherapy regimen, patients are followed up at 2-4 weeks for response, and then every 3 months for 2 years for duration of response and survival.

High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on Chemosensitivity and Genomics/Gene Expression Data

The study will be considered successful (feasibility demonstrated) if it is possible to choose and initiate a combination drug regimen within 21 days in 9 out of 15 patients. With that outcome, there would be 90% confidence that the true feasibility rate is at least 40%.

The secondary objective is to evaluate the response to the chosen therapy. Response will be evaluated using European LeukemiaNet Response Evaluation Criteria in AML (2010 version)

Disease free and overall survival data will be assessed by contacting the referring MD or the patient every three months for the first two years.

National Cancer Institute (NCI)

University of Washington

Assistant Professor, Division of Hematology

Non-hematologic toxicities \>/= grade 3 were recorded from time of assay-guided therapy administration through 14 days after last administration of study therapy Hospitalizations or prolongation of hospitalizations for protocol-scheduled procedures, blood product transfusions, or for social reasons (i.e. awaiting transport home) were not considered SAEs. And hospitalization or prolongation of hospitalizations for fever and/or infection were considered expected, and not considered SAEs.

Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing.

Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations

Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection

Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets

Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets

In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs:

Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin

Chemosensitivity Testing

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Percival

Chemosensitivity Testing and Treatment Initiation Within 21 Days

Percentage of Patients we Are Able to Test and Initiate Treatment Within a 21 Day Period

Treatment (Chemosensitivity Testing, Chemotherapy)

Number of complete remissions + complete remissions with incomplete blood counts

Rate of Complete Remission

Overall survival in months from date of study consent

Survival

Overall Study

Heart and Blood Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Dexamethasone

Dexamethasone acetate

BB 1101

Panobinostat

Ichthammol

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

Histone Deacetylase Inhibitors

Patients receive panobinostat PO on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib IV and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay.

Carfilzomib

Undergo in vitro chemosensitivity testing

Laboratory Biomarker Analysis

Andrew Cowan

This phase II trial studies how well panobinostat, carfilzomib, and dexamethasone work in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carfilzomib and dexamethasone, 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. Using multiple myeloma cells from patients' blood samples, the researchers will do laboratory tests to look at how well each of the drugs, alone and in different combinations, kill multiple myeloma cells. If the laboratory tests work well, they may be used in the future to help plan treatment for future patients.

PRIMARY OBJECTIVE:

I. To correlate in vitro drug sensitivity testing with clinical response by determining the rate of in vitro drug sensitivity to panobinostat, carfilzomib, and dexamethasone singly and in combination, doublets and triplets.

SECONDARY OBJECTIVE:

I. To monitor response rates (partial response \[PR\], very good partial response \[VGPR\], and complete response) using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

EXPLORATORY OBJECTIVE:

I. Progression free survival and overall survival will be assessed for up to 3 years after last dose.

OUTLINE:

Patients receive panobinostat orally (PO) on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib intravenously (IV) and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Panobinostat, Carfilzomib, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

CLBH589DUS108T: Panobinostat With Carfilzomib and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Correlation With In Vitro Chemosensitivity Testing

Assessed using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. Key: 1 = very good partial response (VGPR); 2 = partial response (PR); 3 = minimal response (MR); 4 = stable disease (SD); 5 = progressive disease (PD). Please see IC50 and CI results in the other primary outcome measures.

Multiple myeloma cells are added to assay with panobinostat. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-9.

Multiple myeloma cells are added to assay with carfilzomib. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells.

Multiple myeloma cells are added to assay with dexamethasone. Cell viability and IC50 is determined. IC50 is the inhibitory concentration that kills 50% of cells. Results are reported in concentrations E-6.

Concentration of carfilzomib and panobinostat in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism.

Concentration of panobinostat and dexamethasone in combination leading to 90% growth inhibition of multiple myeloma cells in-vitro. The combination index (CI) is calculated using formula: CI = (\[D1\] in the combination / \[D1\] alone) + (\[D2\] in the combination / \[D2\] alone). Key: CI = 1 no synergy; CI\<1 synergy; CI\>1 antagonism.

SecuraBio

Assistant Professor, Division of Medical Oncology

Only non-hematologic toxicities ≥ grade 3 will be reported as adverse events. Hospitalizations or prolongation of hospitalizations for protocol-schedule procedures, blood product transfusions, or social reasons (i.e. awaiting transport home) will not be considered a SAE.

Patients undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay. Regardless of assay results, patients receive panobinostat PO on days 1, 3, 5, 15, 17, and 19, and carfilzomib IV and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Chemo Assay and Treatment With Panobinostat, Carfilzomib, and Dexamethasone

Age, Customized

Male

Female

Sex/Gender, Customized

Prior therapy regimes

Prior autologous transplant

Revised ISS is the Revised International Staging System, which is used to stage multiple myeloma at diagnosis. It takes into account a patient's albumin, beta-2-microglobulin, lactate dehydrogenase levels, and chromosomal abnormalities detected by FISH to predict survival. There are three stages: I, II, and III. The lower the stage, the longer the progression-free survival.

Revised ISS Stage

Study was limited by lower accrual than expected due to: competing studies, other investigators' treatment preferences, and ultimately, the departure of the initial PI from the institution. Because of PI's departure and lab closure, the study closed to accrual after the 9th patient enrolled. Because only 9 subjects were enrolled and some in-vitro assay results are unavailable, it is difficult to analyze the in-vitro assay results and determine the parameters that predict disease response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia	NCT02551718	Recurrent Acute... Recurrent Acute... Recurrent Acute... Refractory Acut... Refractory Acut... Refractory Acut...	Chemosensitivit... Cytology Specim... Gene Expression... Genetic Variati... In Vitro Sensit...	3 Years -	University of Washington
Panobinostat, Carfilzomib, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma	NCT03256045	Recurrent Plasm... Refractory Plas...	Carfilzomib Chemosensitivit... Dexamethasone Laboratory Biom... Panobinostat	18 Years -	University of Washington

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