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Venetoclax, Dasatinib, Prednisone, and Rituximab for the Treatment of Newly Diagnosed or Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT04872790
Recruitment Status : Not yet recruiting
First Posted : May 5, 2021
Last Update Posted : May 11, 2021
Sponsor:
Collaborators:
AbbVie
Oregon Health and Science University
Information provided by (Responsible Party):
Jessica Leonard, OHSU Knight Cancer Institute

Brief Summary:
This phase I trial studies the effects of venetoclax in combination with dasatinib, prednisone, and rituximab in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia that is newly diagnosed or that has come back (relapsed). Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Anti-inflammatory drugs, such as prednisone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving venetoclax in combination with dasatinib, prednisone, and rituximab may help treat patients with newly diagnosed or relapsed Philadelphia chromosome positive acute lymphoblastic leukemia.

Condition or disease Intervention/treatment Phase
B Acute Lymphoblastic Leukemia Recurrent B Acute Lymphoblastic Leukemia Drug: Dasatinib Drug: Methotrexate Drug: Prednisone Biological: Rituximab Drug: Venetoclax Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and/or a recommended phase II dose (RP2D) of venetoclax in combination with dasatinib.

II. Evaluate the safety of venetoclax in combination with dasatinib by assessing the frequency, type, and severity of adverse events.

SECONDARY OBJECTIVES:

I. Assess preliminary response to venetoclax in combination with dasatinib based on minimal residual disease (MRD) negativity.

II. Estimate progression-free and overall survival.

EXPLORATORY OBJECTIVES:

I. Evaluate the distribution of BCL-ABL fusion sub-types. II. Assess changes in BCL-family dependence. III. Presence of co-occurring leukemia specific mutations.

OUTLINE: This is dose-escalation study of venetoclax.

INDUCTION PHASE: Patients receive prednisone orally (PO) once daily (QD) on days -6 to 21 and taper off days 22-28, dasatinib PO QD days 1-28, venetoclax PO QD days 3-28 or days 3-21, rituximab intravenously (IV) on days 8 and 15, and methotrexate intrathecally (IT) once during week 1 and once during week 3 in the absence of disease progression or unacceptable toxicity.

POST-INDUCTION PHASE: Patients receive dasatinib PO QD days 1-28, venetoclax PO QD on days 1-28 or 1-21, rituximab IV on days 1 and 15, and methotrexate IT on days 1 and 15. Treatment repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with clinical benefit may continue to receive treatment for up to 12 months per the discretion of the physician.

After completion of study treatment, patients are followed up at 4 weeks and then every 12 weeks for up to 1 year.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Dose-Finding Phase I Study of the Oral BCL-2 Inhibitor Venetoclax (ABT-199) in Combination With Standard Induction Therapy, Dasatinib Prednisone, and Rituximab in Adult Patients With Newly Diagnosed and Relapsed Philadelphia Chromosome Positive ALL (Ph+ ALL)
Estimated Study Start Date : August 31, 2021
Estimated Primary Completion Date : May 1, 2025
Estimated Study Completion Date : May 1, 2026


Arm Intervention/treatment
Experimental: Treatment (prednisone, dasatinib, venetoclax, rituximab)

INDUCTION PHASE: Patients receive prednisone PO QD on days -6 to 21 and taper off days 22-28, dasatinib PO QD days 1-28, venetoclax PO QD days 3-28 or days 3-21, rituximab IV on days 8 and 15, and methotrexate IT once during week 1 and once during week 3 in the absence of disease progression or unacceptable toxicity.

POST-INDUCTION PHASE: Patients receive dasatinib PO QD days 1-28, venetoclax PO QD on days 1-28 or 1-21, rituximab IV on days 1 and 15, and methotrexate IT on days 1 and 15. Treatment repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with clinical benefit may continue to receive treatment for up to 12 months per the discretion of the physician.

Drug: Dasatinib
Given PO
Other Names:
  • BMS-354825
  • Dasatinib Hydrate
  • Dasatinib Monohydrate
  • Sprycel

Drug: Methotrexate
Given IT
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039

Drug: Prednisone
Given PO
Other Names:
  • .delta.1-Cortisone
  • 1, 2-Dehydrocortisone
  • Adasone
  • Cortancyl
  • Dacortin
  • DeCortin
  • Decortisyl
  • Decorton
  • Delta 1-Cortisone
  • Delta-Dome
  • Deltacortene
  • Deltacortisone
  • Deltadehydrocortisone
  • Deltasone
  • Deltison
  • Deltra
  • Econosone
  • Lisacort
  • Meprosona-F
  • Metacortandracin
  • Meticorten
  • Ofisolona
  • Orasone
  • Panafcort
  • Panasol-S
  • Paracort
  • Perrigo Prednisone
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisone Intensol
  • Prednisonum
  • Prednitone
  • Promifen
  • Rayos
  • Servisone
  • SK-Prednisone

Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab ABBS
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar JHL1101
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • Rituximab Biosimilar SIBP-02
  • rituximab biosimilar TQB2303
  • rituximab-abbs
  • RTXM83
  • Truxima

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities [ Time Frame: Up to 30 days after initiation of cycle 1 (1 cycle = 28 days) ]
    A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications. In order to be declared a dose-limiting toxicity, an adverse experience must be determined related (definitely, probably, or possibly) to study drug. Point estimates and 95% exact confidence intervals will be reported

  2. Incidence of adverse events [ Time Frame: Up to 90 days after last dose of study drug ]
    Adverse events will be graded and categorized according to the CTCAE v5.0. Point estimates and 95% exact confidence intervals will be reported.


Secondary Outcome Measures :
  1. Rate of complete molecular response (uMRD) [ Time Frame: Up to completion of cycle 3 (1 cycle = 28 days) ]
  2. Duration of complete molecular response (CMR) [ Time Frame: From date of CMR to date of molecular relapse, death or date of last follow-up, assessed up to 12 months after discontinuing study therapy ]
    The proportion of subjects with CMR as previously defined and its 95% exact confidence interval will be estimated using the efficacy analysis set. Will be estimated using the Kaplan-Meier method along with 95% exact confidence interval.

  3. Progression-free survival [ Time Frame: From first dose of dasatinib, to hematologic relapse of the disease or death in first complete response (CR) or complete response with incomplete bone marrow recovery (CRi), assessed up to 12 months after discontinuing study therapy ]
    Will be estimated using the Kaplan-Meier method along with 95% exact confidence interval.

  4. Overall survival [ Time Frame: From first dose of dasatinib to death from any cause, assessed up to 12 months after discontinuing study therapy ]
    Will be estimated using the Kaplan-Meier method along with 95% exact confidence interval.


Other Outcome Measures:
  1. Frequency of BCR-ABL fusion protein subtypes [ Time Frame: Up to 12 months ]
    Descriptive statistics will be used to present the percentage of patients with a p190 vs p210 fusion protein at diagnosis, as measured in tumor tissues (peripheral blood, bone marrow aspirate) collected prior to treatment with venetoclax or dasatinib.

  2. Percent apoptosis (from baseline) following treatment with the various BH3 family member proteins [ Time Frame: Up to 12 months ]
    Descriptive statistics will be used to present measurements made in tumor tissues (peripheral blood, bone marrow aspirate) collected prior to treatment with venetoclax or dasatinib.

  3. Frequency of gene mutations [ Time Frame: Up to 12 months ]
    Descriptive statistics will be used to present measurements made in tumor tissues (peripheral blood, bone marrow aspirate) collected prior to treatment with venetoclax or dasatinib.

  4. Distribution of gene mutations [ Time Frame: Up to 12 months ]
    Descriptive statistics will be used to present measurements made in tumor tissues (peripheral blood, bone marrow aspirate) collected prior to treatment with venetoclax or dasatinib.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must have histologically confirmed diagnosis of pre-B acute lymphoblastic leukemia harboring the t(9;22) translocation (Philadelphia chromosome positive acute lymphoblastic leukemia [Ph+ ALL]). All patients must have a bone marrow biopsy completed during the screening period. Patients with central nervous system (CNS) disease will be included
  • Newly diagnosed subjects must have received no prior treatment for their ALL with the exception of steroids (prednisone, dexamethasone), hydrea or IT methotrexate. Patients may receive up to 6 days of pre-treatment with steroids prior to enrollment during the screening phase
  • Patients with relapsed disease may not have had prior treatment with dasatinib
  • Age >= 18 years. Both men and women and members of all races and ethnic groups will be included
  • Eastern Cooperative Oncology Group (ECOG) status =< 2
  • Must be able to take oral medication
  • Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)

    • Unless considered due to leukemic organ involvement
  • Alanine aminotransferase (ALT) < 2.5 x ULN

    • Unless considered due to leukemic involvement
  • Bilirubin < 1.5 x ULN

    • Unless considered due to leukemic organ involvement
    • Note: subjects with Gilbert's Syndrome may have a bilirubin > 1.5 x ULN per discussion between the investigator and AbbVie medical monitor
  • Subject must have adequate renal function as demonstrated by a calculated creatinine clearance >= 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft-Gault formula

    • NOTE: For subjects that have body mass index (BMI) of > 25 kg/m^2, 24-hour measured creatinine clearance is required
  • Women of childbearing potential must have a negative serum or urine pregnancy test (sensitivity < 25 IU human chorionic gonadotropin [HCG]/L) within 72 hours prior to the start of the study drug
  • Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped. Women of childbearing potential and men with a sexual partner of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy
  • Normal corrected QT (QTc) interval on screening electrocardiogram (EKG) (< 450 ms in men, < 470 ms in women)
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • For newly diagnosed subjects: who have received treatment with cytotoxic chemotherapy, radiotherapy or immunotherapy for their ALL, or prior dasatinib treatment. For relapsed subjects: prior dasatinib treatment
  • Subjects who have received any investigational agents or subjects who are taking investigational or commercial agents or therapies with the intent to treat the subject's malignancy within seven days of enrollment
  • Subjects with chronic myelogenous leukemia (CML) in myeloid blast crisis, Ph+ acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage
  • Subjects with clinically serious infections as determined by the provider requiring ongoing antibiotic therapy. This does not include antibiotic treatment for neutropenic fever
  • Patients with a pleural or pericardial effusion of any grade
  • Subjects with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to dasatinib or other agents used in the study
  • Subjects who have undergone prior allogeneic hematopoietic stem cell transplantation
  • Subject has received the following within 7 days prior to the initiation of study treatment: Strong or moderate CYP3A inducers (such as rifampin, carbamazepine, phenytoin, and St. John's wort); warfarin or inhibitors (such as fluconazole, ketoconazole and clarithromycin
  • Subjects with uncontrolled cardiac illness including but not limited to, symptomatic congestive heart failure, unstable angina pectoris, clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), or pulmonary hypertension
  • Subjects with diagnosed congenital prolonged QT syndrome
  • Pregnant women are excluded from this study because dasatinib is a pregnancy category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dasatinib, breastfeeding should be discontinued if the mother is treated with dasatinib. These potential risks may also apply to venetoclax for which the pregnancy category and risks to the fetus are unknown
  • Participant is seropositive with human immunodeficiency virus (HIV) or has active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).

    • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
    • For patients with evidence of chronic HBV infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
    • Individuals with a history of HCV infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Subjects with invasive malignancy over the previous year except treated early stage carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, completely resected papillary thyroid and follicular thyroid cancers, and localized prostate cancer treated with curative intent with surgery or radiation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04872790


Locations
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United States, Oregon
OHSU Knight Cancer Institute
Portland, Oregon, United States, 97239
Contact: Jessica T. Leonard    503-494-8534    leonard@ohsu.edu   
Principal Investigator: Jessica T. Leonard         
Sponsors and Collaborators
OHSU Knight Cancer Institute
AbbVie
Oregon Health and Science University
Investigators
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Principal Investigator: Jessica T Leonard OHSU Knight Cancer Institute
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Responsible Party: Jessica Leonard, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT04872790    
Other Study ID Numbers: STUDY00022691
NCI-2021-01791 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00022691 ( Other Identifier: OHSU Knight Cancer Institute )
First Posted: May 5, 2021    Key Record Dates
Last Update Posted: May 11, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Prednisone
Cortisone
Rituximab
Antineoplastic Agents, Immunological
Methotrexate
Dasatinib
Venetoclax
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antirheumatic Agents
Anti-Inflammatory Agents
Glucocorticoids
Hormones