A Phase II Study of AT7519M, a CDK Inhibitor, in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia
- Previously documented CLL as defined by the 2008 International Workshop on Chronic
Lymphocytic Leukemia guidelines [Hallek 2008(a)], that is recurrent or relapsed after
previous therapy and that requires treatment.
- Patients must have a life expectancy of at least 12 weeks.
- Age ≥ 18 years.
- ECOG performance status of 0, 1 or 2
- Measurable disease criteria to assess response. Patients must have at least ONE of:
Absolute lymphocyte count ≥ 10 x 10^9/L OR At least one pathologically enlarged lymph node
(≥ 2 x 2 cm) by CT scan
- Previous Therapy Patients must have received at least one, and may have received up
to three prior systemic treatment regimens (single agent or combination therapy),
there is no limit on number of prior regimens.
Patients must have received at least one prior systemic treatment regimen (single agent or
combination therapy). There is no limit on number of prior regimens.
Patients must be ≥ 4 weeks since last dose of systemic therapy (including
investigational). Exceptions to the 4-week interval since last treatment are possible if
prior therapy is non-myelosuppressive or if any treatment-related myelosuppression has
Based on a review of recently published phase II trials of CDK inhibitors in relapsed and
refractory CLL, there does not appear to be sufficient grounds to restrict the number of
previous cycles of systemic chemotherapy. The IND193 investigators do not predict that
this change will affect either the safety or efficacy outcomes of the study drug.
- Not permitted:
- Radioactive Monoclonal Antibody Therapy
- Prior treatment with AT7519M or another CDK inhibitor
- Previous allogeneic stem cell transplant (Note: autologous stem cell transplant is
Patients may have had radiation, provided a minimum of 21 days has elapsed prior to
enrollment. (Exceptions may be made however, for low dose, palliative radiotherapy
Patients must have recovered from any acute toxic effects from radiation prior to
Previous surgery is permitted provided that wound healing has occurred and at least 14
days have elapsed if surgery was major.
- Laboratory Requirements: (must be done within 7 days prior to registration)
Hematology = Absolute neutrophils (ANC) ≥ 1.0 x 10^9/L Platelets = ≥ 75 x 10^9/L
(exception: if ITP secondary to CLL, allow 50 x 10^9/L) Chemistry = Creatinine
clearance* ≥ 50 mL/min Creatine Phosphokinase = (CK or CPK) ≤ UNL Bilirubin = ≤ UNL
AST and ALT = ≤ 2.5 x UNL Potassium, Calcium, Magnesium Within normal limits
- Patient consent must be obtained according to local Institutional and/or University
Human Experimentation Committee requirements. It will be the responsibility of the
local participating investigators to obtain the necessary local clearance, and to
indicate in writing to the NCIC CTG Study Coordinator that such clearance has been
obtained, before the trial can commence in that centre. Because of differing
requirements, a standard consent form for the trial will not be provided but a sample
form is provided as a separate attachment. A copy of the initial REB approval and
approved consent form must be sent to the central office. The patient must sign the
consent form prior to registration. Please note that the consent form for this study
must contain a statement which gives permission for the NCIC CTG and monitoring
agencies to review patient records.
- Patients must be accessible for treatment and follow-up. Patients registered on this
trial must be treated and followed at the participating centre. This implies there
must be reasonable geographical limits (for example: 1 ½ hour's driving distance)
placed on patients being considered for this trial. Investigators must assure
themselves the patients registered on this trial will be available for complete
documentation of the treatment, response assessment, adverse events, and follow-up.
- In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working
days of patient registration.
- Patients with a history of other malignancies, except: adequately treated
non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, other in
situ cancers or other invasive malignancies curatively treated with no evidence of
disease for ≥ 5 years.
- Patients with known CNS involvement by CLL. Tests to investigate CNS involvement are
required only if clinically indicated (i.e. disease suspected on basis of symptoms or
- Patients with clinically suspected or proven progression to high grade lymphoma
(Richter's transformation) or myelodysplasia.
- Patients with known hypersensitivity to the study drug or its components.
- The following are exclusions for enrolment on the study:
1. Pregnant or lactating women. (N.B.: All women of childbearing potential must
have a negative serum or urine pregnancy test within 7 days prior to
2. Men and women of childbearing potential who do not agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of the study participation. (Should a woman
become pregnant or suspect she is pregnant, or should a man father a child,
while participating in this study, she/he should inform the treating physician
- Serious illness or medical condition which would not permit the patient to be managed
according to the protocol, including, but not limited to:
1. history of significant neurologic or psychiatric disorder (e.g. uncontrolled
psychotic disorders) which would impair the ability to obtain consent or limit
compliance with study requirements;
2. active uncontrolled or serious infection (viral, bacterial or fungal);
3. pulmonary disease requiring oxygen;
4. known HIV infection or other immune deficiency disorders (except for CLL);
5. other medical conditions that might be aggravated by study treatment
- Patients with pre-existing cardiovascular conditions and/or symptomatic cardiac
dysfunction as follows:
1. Significant cardiac event (including heart failure or ischemia) within 3 months
of entry or any cardiac disease that, in the opinion of the investigator,
increases risk for ventricular arrhythmia
2. Any family or personal history of ventricular arrhythmia, which was symptomatic
or required treatment (CTC grade 3). This includes: multifocal PVCs, bigeminy,
trigeminy, ventricular tachycardia)
3. Uncontrolled hypertension (systolic blood pressure of 150 mmHg or higher or
diastolic blood pressure of 95 mmHg or higher)
4. A previous history of drug induced QTc prolongation (defined as a QTc interval
equal to or greater than 500 msec) or other significant ECG abnormalities
5. Congenital long QT syndrome
6. QT and QTc, unmeasurable or > 460 msec on screening ECG
7. Left ventricular ejection fraction (LVEF) of less than the institution's lower
limit of normal (LLN) measured by MUGA or echocardiogram
- Patients who are currently receiving treatment with agents with a known risk of
Torsades de Pointes. (see http://torsades.org [list #1]). However, patients may be
enrolled on study if treatment with such agents is stopped ≥ 7 days prior to first
dose of AT7519M.
- Patients with pre-existing peripheral neuropathy (sensory and/or pain) > grade 2.
- Patients with uncontrolled auto-immune hemolytic anemia (AIHA) and/or auto-immune
thrombocytopenia (ITP) who require active treatment.