Summary Basis of Decision for Clolar ®

3.3.1 Pharmacodynamics

Inhibition of DNA synthesis in leukaemia blast cells was measured in 4 patients who received doses of 11.25, 15, 40, or 52 mg/m² clofarabine. Generally, DNA synthesis rapidly declined, however a 10-50% recovery was observed 24-hours later. The recovery of DNA synthesis appeared to be related to the clofarabine dose administered. At the maximum tolerated dose (52 mg/m²), the inhibition of DNA synthesis was maintained throughout therapy. In another study, administration of 52 mg/m² clofarabine resulted in a significant, rapid reduction of peripheral leukaemia cells in 94% (31/33) of paediatric ALL patients who had measurable absolute blast counts.

A study was conducted to determine whether or not the inhibition of DNA synthesis is dose-dependent. At a dose of 22.5 mg/m²/day, a 60% decrease in DNA synthesis was observed after 3-4 days treatment followed by a partial recovery period before the second dose of clofarabine. At 30 mg/m²/day, the inhibition of DNA synthesis was almost complete but not sustainable. Only at 55 mg/m²/day, was the inhibition of DNA synthesis completely sustainable.

3.3.2 Pharmacokinetics

Absorption

The PK of clofarabine were studied in 22 ALL paediatric patients who received daily administration of 52 mg/m² clofarabine over a period of 2 hours by IV infusion for 5 consecutive days. Maximum plasma clofarabine concentrations were generally achieved by the end of the infusion, ranging from 141-838 ng/mL on Day 1 and 214-1390 ng/mL on Day 5. Plasma concentrations appeared to decline in a biphasic manner. Little accumulation was seen on Day 5 compared to Day 1.

The maximum plasma concentration (C_max) was inversely proportional to the patient's body weight. Longer infusion times should be considered for smaller children with a body weight <20 kg.

Distribution

Clofarabine was only 47% bound to human plasma proteins, predominantly to albumin. Clofarabine showed high tissue distribution. Volume of distribution at steady-state was estimated to be 122 L/m² in patients with ALL. Minimum accumulation was seen with once-daily dosing in the clinical studies.

Metabolism

Clofarabine is a prodrug and exerts its activity through its active metabolites. Clofarabine is transported into target cells by both diffusion and facilitated diffusion. Intracellular clofarabine is mono-phosphorylated by deoxycytidine kinase and then serially phosphorylated by other kinases to form clofarabine triphosphate, the active moiety. The metabolic pathways for clofarabine triphosphate remain unknown.

In vitro studies in isolated human hepatocytes showed that clofarabine does not induce hepatic enzymes nor does clofarabine inhibit CYP. In isolated human hepatocytes, clofarabine showed very limited metabolism suggesting that CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine.

Excretion

The major route of clofarabine elimination is by renal excretion of unchanged drug. An average of 58% of the dose was excreted within 24 hours after a single-dose administration in paediatric patients with ALL. The mean renal clearance was 15.1 L/hour which, after correction for protein binding, was much greater than the glomerular filtration rate in humans. Hence, clofarabine showed evidence of filtration and tubular secretion as kidney elimination mechanisms.

3.3.3 Clinical Efficacy

The clinical efficacy of Clolar was evaluated in two Phase II, open-label, non-randomized, single-arm studies in paediatric patients who experienced multiple relapses or were refractory to front-line therapy.

The pivotal, Phase II study (Study CLO-212) was conducted in 61 paediatric patients (≤21 year of age at initial diagnosis) who were previously treated with a median of 3 prior induction regimens. Patients received a dose of 52 mg/m² Clolar over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles (median 2 cycles). Approximately one-third of the patients received at least 1 prior transplantation, and 57% were refractory to the last therapeutic regimen. The primary endpoint was the overall remission rate determined by the sum of the number of patients with either a CR or CRp. Secondary endpoints included overall survival, and duration of remission. Twelve of 61 ALL patients achieved CR or CRp. The overall remission rate was 20%. Of those who were refractory to their most recent prior regimen, the overall remission rate was 17%. Responses were observed in patients with both T-cell and B-cell lineage ALL, and in patients who had a prior haematopoietic stem cell transplant (HSCT). A total of 31% patients achieved at least a partial response. Ten of the 61 ALL patients proceeded to HSCT, with no apparent increase in transplantation-related toxicity. The median survival was 12.9 weeks in all patients. The median overall survival was 66.6 weeks in patients who achieved a CR or CRp.

The other Phase II study (Study BIOV-111) was conducted in 71 paediatric patients (≤21 year of age at initial diagnosis) who failed to achieve primary response on conventional treatment regimens, or failed to achieve a response at first relapse. Patients were also eligible at second and subsequent relapse. Patients received a dose of 52 mg/m² Clolar over 2 hours for 5 consecutive days, repeated every 21±7 days, for up to 12 cycles. The 65 patients who received one full 5-day course of Clolar were included in the primary efficacy analyses. The primary endpoint was the overall remission rate, same as the study above. Additional study endpoints included partial response, evaluation of the duration of remission, overall survival, the number of patients proceeding to HSCT, and the time to bone marrow transplantation. The overall remission rate was 23.1% and 31.3% in patients who completed 1 and 2 treatment cycles, respectively. A CR was observed in 3 (4.6%) patients, two of whom received a bone marrow or stem cell transplant following clofarabine treatment. Seven (9.9%) of the patients received a bone marrow transplant or peripheral blood stem cell transplant after the first dose of Clolar. Median survival among transplant recipients was 358 days. For three patients, the CR survival times were censored at 358, 941, and 954 days. Although the study was uncontrolled, the overall remission rate, transplant rate, overall survival, and survival among patients with CR indicate that Clolar treatment has a clinically important effect in this patient population.

3.3.4 Clinical Safety

The safety data for 115 paediatric patients, with relapsed or refractory ALL (n=70) or acute myeloid leukemia (AML, n=45), who received at least one infusion of Clolar at 52 mg/m² were combined into an integrated database. The analysis of data identified groups of AEs that characterize the safety profile of Clolar in this population. Foremost were haematologic toxicities and infections resulting from the immunosuppressive effect of Clolar. Other significant groups of AEs observed for Clolar were found in the hepatobiliary, renal, and gastrointestinal organ systems. In addition, 11 events of tumour lysis syndrome, capillary leak syndrome or systemic inflammatory response syndrome were reported. The most common toxicities observed during exposure to Clolar were gastrointestinal system AEs (including vomiting, nausea, and diarrhoea), adverse haematologic effects (including anaemia, leukopaenia, thrombocytopenia, neutropaenia, and febrile neutropaenia), and infection.

The safety profile of Clolar is difficult to delineate considering the complicated medical history presented by most patients in the integrated safety database. Many factors could potentially affect the interpretation and assignment of causality for AEs including underlying infection, concomitant medications, progressive disease, and organ damage associated with prior high-dose chemotherapy and total body irradiation for transplant. Due to prolonged immuno- and myelosuppression from prior therapies, this population was susceptible to a wide range of illnesses, particularly fungal or bacterial infections. Most patients entered a study with at least one concurrent infection and the majority of patients experienced at least one infection during treatment with Clolar.

Haematologic toxicity was frequently observed during exposure to Clolar. Virtually all patients had pre-existing haematologic and chemistry abnormalities. These toxicities included the onset or worsening of anaemia, leukopaenia, thrombocytopenia, neutropaenia, and febrile neutropaenia. Febrile neutropaenia was the most common grade 3 AE considered related to the study drug. Fifty percent of the patients in the integrated safety database reported a serious adverse event (SAE) of febrile neutropaenia.

The majority (83%) of patients experienced at least one infection during treatment with Clolar. Post-baseline infections were generally grade 3 and included cellulitis, bacteraemia, Herpes simplex, Herpes zoster, catheter-related infection, clostridium colitis, and pneumonia. There was a smaller incidence of grade 4 infections (10/95 patients) observed in the safety population. These infections included bacterial sepsis, enterococcal infection, Escherichia sepsis, fungal infection, fungal sepsis, pneumonia fungal, pneumonia, septic shock, sepsis, Staphylococcal bacteraemia, Staphylococcal sepsis, systemic mycosis and varicella. Infections that were considered to be a contributing factor in the deaths of 8 patients were: sepsis, septic shock, and pneumoniae. However, only one grade 5 infection (septic shock) was considered related to Clolar.

The liver was known to be a target organ of toxicity based on earlier non-clinical and Phase I data. Approximately 25% of patients experienced hepatobiliary AEs during treatment with Clolar. The most frequent hepatobiliary AEs observed included jaundice and hepatomegaly. Three patients experienced hepatic AEs considered related to study drug resulting in discontinuation for one patient and the deaths of two patients.

Although few patients entered the study with elevated AST or ALT, the incidence of grade 3 or 4 AST or ALT following Clolar treatment ranged from 36% to 44%, respectively. A total of 13.2% of patients reported grade 3 or 4 total bilirubin post-baseline. Almost half of the patients overall experienced the onset or worsening of elevated total bilirubin during treatment with Clolar.

Adverse events in the renal system organ class (SOC) are significant because clofarabine is known to be eliminated by the kidney via glomerular filtration and tubular secretion. Approximately one third of the patients reported an AE in the renal and urinary system. Overall, a total of 53% (61/115) of the patients experienced the onset of or worsening of elevated creatinine. The most frequently reported renal AE was haematuria which may reflect the thrombocytopenia that was common in many of these patients. Nephrotoxic medications, tumour lysis, and tumour lysis with hyperuricaemia may contribute to renal toxicity.

A majority of the paediatric patients in the integrated database reported at least one AE in the gastrointestinal disorders SOC, and the AEs most frequently observed were vomiting and nausea. Other frequent gastrointestinal AEs were diarrhoea, abdominal pain and constipation. Most of these events were grade 1 or 2 in severity and rarely met the criteria for an SAE.

A capillary leak syndrome was reported as a side effect of Clolar in several patients. It may result from the release of cytokines and may also reflect either direct or indirect damage to endothelial cells. However, underlying medical conditions, (e.g., fungal infections, effusions, and cardiovascular abnormalities), toxicities from prior therapies, infections, or disease progression, may also cause a capillary leak-like syndrome. The signs and symptoms of cytokine release (e.g., tachypnaea, tachycardia, hypotension, pulmonary eodema) could progress to systemic inflammatory response syndrome (SIRS), capillary leak syndrome and multi-organ dysfunction.

Forty-nine percent of patients experienced at least one cardiac AE. Since some cardiotoxicity had been observed in the non-clinical rat studies, a paediatric cardiologist reviewed all of the echocardiograms (ECHOs). The cardiologist concluded that direct cardiotoxicity of clofarabine could not be completely ruled out, but observed that patients who experienced the majority of cardiac function changes were frequently ill from disease progression, sepsis, or other substantial adverse medical conditions when the ECHOs were performed.

Thirty-three of 115 patients (29%) reported an AE of hypotension. Five events (four Grade 3 and one Grade 4) were Clolar-related. The occurrence of treatment-emergent hypotension was usually associated with severe or systemic infections and pre-existing medical conditions.

Safety data from Study BIOV-111 were not included with the integrated dataset. The spectrum of AEs seen in this study was consistent with the known safety profile of Clolar, and did not give rise to any new concerns specific to the use of Clolar in a paediatric population. The safety profile of Clolar is also supported by the post-market safety profile of approximately 5000 patients since the drug was first marketed in the United States in December 2004. Considering the concordance of AE profiles across Study BIOV-111, the integrated safety summary, and in the post-marketing setting, Clolar demonstrated an acceptable safety profile in heavily pre-treated paediatric patients with poor prognosis.