7-Cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Endpoint summary

Description of key information

Repeated dose toxicity study; Test duration: 15 weeks with 4 weeks recovery

The dose regimen was: 3 weeks on / 1 week off (like clinical)

Rats M: 25, 75, 150 mg/kg; F: 50, 150, 300 mg/kg

Route of administration: Oral

Effects

≥ 25 mg/kg/day M: hematology changes consistent with decreased hematopoiesis, decrease in the thymus weights were observed in males

≥ 75 mg/kg/day M: kidney, testes/epididymis, hematopoietic system (thymus, lymph nodes, bone marrow)

150 mg/kg/day M: lung, liver,

≥ 150 mg/kg/day F: lymph nodes

Based on the severity of findings in the testes of males given ≥75 mg/kg/day and in the lung of males given 150 mg/kg/day, these observations were considered adverse.

NOAEL

M: 25 mg/kg/day; F: 300 mg/kg/day

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because relevant human exposure can be excluded as based on the provided thorough and rigorous exposure assessment

Justification for type of information:

The personal protective measure may be adapted appropriately when working in closed systems or under laboratory conditions.
Regular cleaning of equipment, work area and clothing.
No open handling without using reliable equipment. One technical barrier between substance and employee resp. environment.
Restricted and controlled access for trained personnel only.
Designated washing, changing and shower facilities must be available.
Internal working procedures available to personnel covering personal hygiene, decontamination /cleaning, consideration of worst case incidents, spills, emergency, alarms, waste disposal and maintenance.
Personnel comprehensively instructed, highly trained and experienced. Regular refresher training established including appropriate record keeping.
Equipment and protective garments must either be decontaminated or properly contained for disposal before leaving the area.
Disposable protective equipment is to be decontaminated before removal (decontamination shower).
Open Handling Respiration : Full face mask (EN136)
Filter : P3 (EN143)
Eye : Yes, by face mask
Hand : Normal length chemical-mechanical-resistant gloves (EN374/EN388)
worn over disposable gloves
Glove Material : Nitrile
Breakthrough time: 240 min
Thickness: 0.4 mm
Additional protection : Disposable dust-proof suit (EN465, type 4) worn over long underwear
Disposable boot covers, conductive

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

System:

urinary

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

As of 24-Apr-2014, 132 patients have been treated with single agent LEE011 in the FIH phase I study; 85 patients have been treated in the dose escalation part and 47 patients in the dose expansion part of the study.

Patients with advanced solid tumors or lymphomas were treated with increasing doses of LEE011 orally, once daily (qd) for 21 days followed by a 1-week rest (28-day cycle). Doses ranging from 50 mg to 1200 mg were evaluated on this schedule. In addition, continuous dosing of LEE011 at 600 mg was evaluated (qd for 28 days of a 28-day cycle).

Treatment has been discontinued in 111 (84%) patients; the primary reasons for treatment discontinuation were: disease progression (96 [72%] patients); AEs (8 [6%] patients); withdrawal of consent (3 [2%] patient); and loss to follow up (1 [1%] patient). Out of the 114 evaluable patients, 3 partial responses were observed at the 600 mg dose level; one each in BRAF/NRAS wild type with CCND1 amplified melanoma, and head and neck acinar carcinoma with CDKN2A loss (both on the 3 weeks on/1 week off regimen), and ER+/HER2-, PIK3CA mutant, CCND1 amplified breast cancer (on the continuous daily dosing regimen). This study is currently evaluating a dosing schedule with LEE011 400 mg continuous dosing, as well as the safety and PK of the oral solution formulation.

The dose of 50 mg was done based on the 4-wk tox data- in oncology the NOAEL is not used for the determination of the starting dose. In our case:

Following FDA guidance, if the starting dose is based on the 4 week GLP toxicology study in the rat, the starting dose in patients is 1/10th of 900 mg/m2/day or 90 mg/m2/day. This dose is relatively conservative since, as noted above, the 900 mg/ m2/day dose was not associated with severe toxicity in the rat. The safety of the 90 mg/ m2/day starting dose is further supported by the 4 week GLP toxicology results in the dog, which identified a significantly higher dose, 400 mg/m2/day, to be the MTD. Assuming that the average patient has a body surface area of 1.7 m2, the starting dose for the first-in-human (patient) trial should be 90 mg/m2 x 1.7 m2 = 153 mg po q day. This dose will be rounded down to 150 mg, given the available dose strengths. However, in vitro studies indicate that LEE011 is a time-dependent inhibitor of CYP3A and therefore has the potential to inhibit its own metabolism and to reduce its own clearance. SimCyp modeling suggests that at a dose of 150 mg/day LEE011’s exposure increases from 1.4 to 3-fold due to this time-dependent inhibition of CYP3A. Therefore, to account for this potential effect, the starting dose is correspondingly reduced by a factor of 3, to 50 mg/day.

Serious adverse events with a suspected causal relationship with LEE011 are: Anaemia, Febrile neutropenia, Neutropenia, Thrombocytopenia, Diarrhoea, Nausea, Generalized oedema, Herpes simplex, Blood creatinine increased.

Justification for classification or non-classification

The effects of LEE011 on the bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation) and testes (atrophy) are considered to be related to the pharmacological inhibition of cell replication in these tissues due to CDK4/6 inhibition. An increased number of ovarian corpora lutea was observed in a single female dog in the 4-week toxicity study at the highest dose tested and this effect could also be related to the pharmacology of LEE011 (arrest of estrous cycle). The liver, bile system and gall bladder and the kidney were identified as additional target organs of toxicity which are not likely related to the primary pharmacology of LEE011. Inflammatory changes in the lungs of dogs were considered secondary to aspiration of test-article and are indicative of the irritant potential of the formulated test-article in the respiratory tract.