FAQs

Response Rates
Dosing & Administration
Safety
Managing Side Effects

Response Rates

What were the characteristics of the study population, relative to prior regimens?

All patients had disease that had relapsed after two or more prior therapies and/or was refractory to two or more prior therapies.

In the phase 2 study, approximately 94% of patients (46 of 49) had received 2 to 4 prior regimens. 30.6% of patients (15 of 49) had undergone at least 1 prior transplant.

How were CR, CRp, and PR defined?

Complete remission (CR) was defined as no circulating blasts or extramedullary disease, <5% bone marrow blasts, recovery of peripheral blood counts (platelet count >100 x 10⁹/L and absolute neutrophil count [ANC] > 1.0 x 10⁹/L).

Complete remission without platelet recovery (CRp) was defined as meeting all criteria of CR except for recovery of platelet counts to >100 x 10⁹/L.

Partial response (PR) was defined as no circulating blasts, ≥5% and ≤25% bone marrow blasts, and the appearance of normal progenitor cells or M1 bone marrow that did not qualify for CR or CRp.

What were the response rates after treatment with Clolar?

In the phase 2 study, over 30% of patients treated with Clolar achieved a complete or partial response.

• 12.2% (6/49) achieved a CR (95% confidence interval: 4.6-24.8)
• 8.2% (4/49) achieved a CRp (95% confidence interval: 2.3-19.6)
• 10.2% (5/49) achieved a PR (95% confidence interval: 3.4-22.2)

How many patients went on to transplant?

40% (6/15) of patients who responded to treatment with Clolar were able to undergo post-treatment bone marrow transplant (transplantation rate was not a study endpoint).

Were responses seen in T lineages?

Yes, responses were seen in both pre-B-cell and T-cell immunophenotypes of ALL. For more response data, see the Study Data section.

Were the responses durable?

Six of 15 patients who responded to treatment with Clolar underwent post-treatment transplantation, and response duration could not be measured. Response durations were assessed in the remaining 9 patients who were not transplanted.

Five of those patients achieved a CR, and their response durations were: 43, 50, 82, 93+, and 160+ days. One patient achieved a CRp with a response duration of 32 days. Three patients achieved a PR; their response durations were 7, 16, and 21 days.

For more response data, see the Study Data section.

Dosing & Administration

What is the recommended dosing schedule for Clolar?

Clolar should be administered to pediatric patients at 52 mg/m²/day by IV infusion over 2 hours for 5 consecutive days. Treatment should be repeated every 2 to 6 weeks based on response, toxicity, and following recovery or return to baseline organ function. This dosage is based on the patient’s body surface area (BSA), which is calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. Clolar has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution.

Safety and efficacy have not been established in adults. Limited phase 2 data indicate adults do not tolerate the pediatric dose; a trial performed in highly refractory and/or relapsed adult patients with hematologic malignancies studied a dose of 40 mg/m²/day administered as a 1 to 2 hour IV infusion for 5 consecutive days every 28 days.

Are any premedications recommended prior to Clolar administration?

Antiemetics should be considered to prevent possible nausea/vomiting. Prophylactic steroids (e.g., 100 mg/m² hydrocortisone on days 1 through 3) may be of benefit in preventing signs or symptoms of systemic inflammatory response syndrome (SIRS)/capillary leak syndrome (e.g. tachypnea, tachycardia, hypotension, pulmonary edema). If hyperuricemia is expected, allopurinol should be administered prophylactically.

Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered.

Are there any hydration recommendations associated with Clolar?

Yes, physicians are encouraged to give continuous IV fluids throughout the 5 days of administration with Clolar to prevent dehydration and to reduce the effects of tumor lysis syndrome and other adverse events.

How should Clolar be prepared for administration?

Clolar should be filtered through a sterile 0.2 µm syringe filter and then further diluted prior to IV infusion. The resulting admixture may be stored at room temperature but must be used within 24 hours of preparation. Clolar can be diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP.

What should be done with any unused drug?

Since Clolar contains no preservatives, any unused drug should be discarded in a closed container appropriate for waste disposal of chemotherapeutic agents.

Can other drugs be infused through the same IV line as Clolar?

To prevent drug incompatibilities, no other medications should be administered through the same IV line; the IV line should be completely flushed before a second medication is given through the line.

For more information, see the Clolar full prescribing information.

Safety

Note that Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Will Clolar cause bone marrow suppression?

Suppression of bone marrow function should be anticipated with Clolar treatment. This is usually reversible and appears to be dose dependent. The use of Clolar is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with Clolar.

What is the risk of tumor lysis syndrome and how can it be treated?

Clolar is a chemotherapeutic agent with a rapid onset of action. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Therefore, all patients should be watched closely for early signs and symptoms of tumor lysis syndrome (such as nausea, vomiting, diarrhea, muscle cramps, arrhythmias, hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia) that could develop into SIRS/capillary leak syndrome (e.g. tachypnea, tachycardia, hypotension, and pulmonary edema). Clolar should be discontinued immediately in the event of clinically significant signs and symptoms of SIRS or capillary leak, either of which can be fatal, and the use of steroids, diuretics and albumin considered.

Clinicians are encouraged to give continuous IV fluids throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse events. If signs and symptoms of tumor lysis syndrome are anticipated or manifest, aggressive hydration and hypouricemic agents (allopurinol) should be considered.

What is the risk of cytokine release and how can it be treated?

The use of anti-metabolite medications can result in a rapid release of cytokines. Patients should be monitored for early signs and symptoms of cytokine release, such as hypotension, tachycardia, tachypnea, and pulmonary edema. Prophylactic steroids (e.g. 100 mg/m² hydrocortisone on days 1 through 3) may be of benefit in preventing the signs and symptoms of cytokine release. Cytokine release can progress into more serious conditions, such as SIRS and capillary leak syndrome—and, ultimately, organ failure. Clolar should be discontinued immediately in the event of clinically significant signs and symptoms of SIRS or capillary leak, either of which can be fatal, and the use of steroids, diuretics and albumin considered.

What type of monitoring should be performed during treatment with Clolar?

Because of the pre-existing immunocompromised condition of most patients, and the rapid reduction in peripheral leukemia cells and the prolonged neutropenia that can result from treatment with Clolar, nurses should closely evaluate and monitor patients for signs and symptoms of infection, tumor lysis syndrome, and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into SIRS/capillary leak syndrome, and organ dysfunction. Careful hematologic monitoring during therapy is important. Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. The respiratory status and blood pressure should be closely monitored during infusion of Clolar.

What about hepatic and renal impairment?

Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. Severe hepatotoxic events have been reported in an ongoing, phase 1/2 clinical trial investigating Clolar in combination with etoposide and cyclophosphamide in pediatric patients with relapsed or refractory acute leukemia. This study found that patients who had previously received a hematopoietic stem cell transplant may be at higher risk for hepatotoxicity.

For more information on safety, please see the Safety section, or see the Clolar full prescribing information.

Managing Side Effects

What steps can be taken to manage nausea, vomiting, and diarrhea associated with Clolar therapy?

For nausea and vomiting, premedication with antiemetics may be considered. Patients should be encouraged to drink plenty of fluids in order to avoid dehydration. Parents, caregivers, and patients should be educated to watch for any significant decrease in urination, or dizziness, lightheadedness, or fainting spells, and report these observations to their healthcare team immediately.

Anxiety and/or agitation have been associated with the administration of Clolar. How should this be managed?

Some pediatric patients may experience restlessness, agitation, and anxiety during the infusion. If this occurs, immediately slow the infusion and inform the oncologist. Anxiolytics and/or antihistamines have been used to control anxiety during Clolar infusions. In some patients, premedication with an antianxiety agent may be considered prior to the next dose.

Hand-foot syndrome has been observed in a few children receiving Clolar. What can be done about it?

Hand-foot syndrome generally is experienced initially as a tingling feeling a few days after initiation of therapy and progresses to redness, dryness, and possible flaking of skin on hands and/or feet. Symptomatic relief may be achieved by lightly applying moisturizers to minimize dryness and flaking. Steroids or antihistamines may also be considered.

For more information, see the Clolar full prescribing information.

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Indication

Clolar is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

Important Safety Considerations

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome, and organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered.

The most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting (grade 3: 8%; grade 4: 1%), nausea (grade 3: 15%; grade 4: 1%), and diarrhea (grade 3: 10%); hematologic effects, including anemia (grade 3: 70%; grade 4: 18%), leukopenia (grade 4: 99%), thrombocytopenia (grade 3: 36%; grade 4: 64%), neutropenia (grade 3: 3%; grade 4: 7%), and febrile neutropenia (grade 3: 53%; grade 4: 3%); and infection (grade 3: 56%; grade 4: 18%).

Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Left ventricular systolic dysfunction was also noted. Since Clolar is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of Clolar administration. In addition, since the liver is a known target organ for Clolar toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided.

Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been observed in patients treated with Clolar. Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections.

Pericardial effusion was a frequent finding in these patients on post-treatment studies. Careful hematologic monitoring during therapy is important. Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. Severe hepatotoxic events have been reported in an ongoing, phase 1/2 clinical trial investigating Clolar in combination with etoposide and cyclophosphamide in pediatric patients with relapsed or refractory acute leukemia. This study found that patients who had previously received a hematopoietic stem cell transplant may be at higher risk for hepatotoxicity.

Patients receiving Clolar may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breastfeeding while receiving treatment with Clolar.

For more information, please consult the Full Prescribing Information (PDF).