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About
This phase II trial studies how well sotrastaurin acetate works in treating patients with chronic lymphocytic leukemia, small lymphocytic leukemia, prolymphocytic leukemia, or Richter's transformation that has returned or that does not respond to treatment. Sotrastaurin acetate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Full description
PRIMARY OBJECTIVES:
I. To determine the objective clinical response rate of AEB071 (sotrastaurin acetate) treatment in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL)/Richter's transformation (RT).
SECONDARY OBJECTIVES:
I. To determine the feasibility and tolerability of long-term administration of a fixed dose of AEB071 in patients with relapsed or refractory CLL/SLL/PLL.
II. To examine select downstream pharmacodynamic effects in this population of patients after receiving AEB071 including assessment of the wingless-type MMTV integration site family (WNT) signaling pathway.
III. To determine the feasibility and tolerability of AEB071 treatment in patients with relapsed or refractory mantle cell lymphoma (MCL) as well as to gain preliminary data regarding efficacy in this patient population.
TERTIARY OBJECTIVES:
I. Determine the proportion of patients with select germline and somatic deoxyribonucleic acid (DNA) alterations, including in the B-cell receptor (BCR) pathway.
II. Determine how mutational and transcriptional status in key genes affects response to this therapy and may have affected response to prior therapies.
OUTLINE:
Patients receive sotrastaurin acetate orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then at least every 3 months thereafter.
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Inclusion criteria
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Life expectancy >= 2 months
Appropriate histologic diagnosis (a) or (b):
(a) Histologically documented diagnosis of intermediate or high risk CLL/SLL, B-PLL, and RT arising from CLL/SLL according to the 2008 guidelines, meeting criteria for active disease requiring treatment:
Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia)
Massive (>= 6 cm below the costal margin), progressive or symptomatic splenomegaly
Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
Constitutional symptoms including any of the following:
Need for cytoreduction prior to stem cell transplantation
(b) Pathologically documented MCL [defined as either t(11;14) or overexpression of cyclin D1] for the MCL pilot study
Relapsed after or refractory to at least one prior therapy
Willingness to undergo all study-related evaluations and procedures
Ability to understand and willingness to execute a written informed consent document
Exclusion criteria
Prior therapy as follows:
Failure to recover toxicity from prior chemo- or radiotherapy to grade 1
Known active leukemia or lymphoma of the central nervous system (CNS) requiring therapy
Inadequate bone marrow function/hematopoietic reserve, except in the case of documented bone-marrow involvement: absolute neutrophil count (ANC) < 1 x 10^9/L
Inadequate bone marrow function/hematopoietic reserve, except in the case of documented bone-marrow involvement: platelets < 30 x 10^9/L
Serum total bilirubin > 2 x ULN (upper limit of normal)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN, or > 5 x ULN if CLL/lymphoma is present in the liver
Estimated glomerular filtration rate (GFR) < 30 mL/min
Patients who are receiving treatment with medications that are known to be strong inducers or inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) and CYP3A4/5 substrates with QT prolongation risk that cannot be discontinued prior to study entry
Clinically significant cardiac diseases, including any of the following:
History of another malignancy that limits survival to less than 2 years in the estimate of the investigator; basal and squamous cell cancers of the skin, or squamous cell carcinoma of the cervix in situ, which were completely resected or otherwise cured, or localized prostate cancer (Gleason < 5) are eligible
Gastrointestinal dysfunction, including motility or malabsorption syndromes or inflammatory bowel disease which could limit absorption of AEB071
Known human immunodeficiency virus (HIV) positivity, or active hepatitis B or C infection with detectible viral nucleic acid in the blood; testing for these viruses is not a required part of screening
Severe systemic infections requiring intravenous antibiotics within the two weeks prior to initiation of AEB071
Lactating or pregnant
Women of child-bearing potential or male partners of women of child-bearing potential who will not agree to use highly effective method of contraception throughout the entire study period and for a minimum of 5 terminal half-lives of AEB071 (approximately 36 hours) after the last dose of study drug; highly effective contraception methods include:
Total abstinence or
Male or female sterilization or
Combination of any two of the following (a+b or a+c or b+c):
Any other life-threatening illness or medical condition that, in the opinion of the investigator, could compromise the safety of the patient or interfere with analysis of study endpoints
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0 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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