A Phase II Study of AT7519M, a CDK Inhibitor, in Patients With Relapsed Mantle Cell Lymphoma
- Histologically documented mantle cell lymphoma non-refractory to prior therapy.
Diagnosis of mantle cell lymphoma should be confirmed by the local institution's
- Presence of clinically and/or radiologically documented disease. At least one site of
disease must be bidimensionally measurable using CT or MRI performed in the 3 weeks
prior to study enrolment. Bone lesions are not considered to be bidimensionally
Minimum size of at least ONE lesion must be as follows: (must be done within 21 days prior
to registration) Lymph nodes (measured by spiral CT scan) > 1.5 cm x 1.5 cm or
Other non-nodal lesions:
MRI ≥ 1 cm x 1 cm CT scan ≥ 1 cm x 1 cm Physical exam ≥ 1 cm x 1 cm (e.g. skin lesion,
- Patients must have a life expectancy of at least 12 weeks.
- Age ≥ 18 years.
- ECOG performance status of 0, 1 or 2 (see Appendix II).
- Previous Therapy Patients must have received at least one, and up to three prior
systemic chemotherapy regimens (high dose chemotherapy with autologous stem cell
support is permitted but this must be counted as one line of therapy) but must NOT
have shown disease progression while receiving chemotherapy or within 1 month of last
dose of most recent therapy (i.e. must be non-refractory).
Patients must be ≥ 4 weeks since last dose of systemic therapy (including
investigational). As noted, 1-3 previous chemotherapy regimens may have been given. NB:
The same chemotherapy combination given for first line therapy and second line therapy is
considered two regimens. Exceptions to the 4-week interval since last treatment are
possible if prior therapy is non-myelosuppressive or if any treatment-related
myelosuppression has resolved.
- Radioactive Monoclonal Antibody Therapy
- Prior treatment with AT7519M or another CDK inhibitor
- Previous allogeneic stem cell transplant (Note: autologous stem cell transplant is
permitted) Prior rituximab or bortezomib treatment is permitted, but they must be
counted as systemic therapy regimens if given as single agents.
Patients may have had radiation, provided a minimum of 21 days has elapsed prior to
enrollment. Patients must have recovered from any acute toxic effects from radiation prior
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 109/L Platelets ≥ 75 x 109/L Chemistry
Serum creatinine ≤ UNL Bilirubin ≤ UNL AST and ALT ≤ 2.5 x UNL Potassium, calcium,
magnesium - Within normal limits Creatine Kinase (CK or CPK) ≤ UNL
- Patient consent must be obtained according to local Institutional and/or University
Human Experimentation Committee requirements. The patient must sign the consent form
prior to registration.
- 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, adverse events, response assessment 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, or other
solid tumours curatively treated with no evidence of disease for > 5 years.
- Patients with known CNS involvement by lymphoma. Tests to investigate CNS involvement
are required only if clinically indicated (i.e. disease suspected on basis of
symptoms or other findings).
- 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;
3. pulmonary disease requiring oxygen;
4. known HIV infection or other immune deficiency;
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 symptomatic heart failure or angina) within
3 months of entry or any cardiac disease that, in the opinion of the
investigator, increases risk for ventricular arrhythmia.
2. Any 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 significant QTc prolongation (defined as a
QTc interval equal to or greater than 500msec) or causing significant ECG
5. Congenital long QT syndrome
6. QT and QTc, unmeasurable or > 460 msec on screening ECG
7. Left ventricular ejection fraction 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.