Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as clofarabine (IV formulation), clofarabine (oral formulation), Clolar®, Clofarex, Evoltra, CAFdA, Cl-F-ara-A, tradename US = Clolar
Clofarabine · 22 trials · 22 indications
Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 calculated strata. OS was defined as the number of months from date of randomization until date of death due to any cause.
Overall survival (OS) for the Full Analysis Set (FAS) and for the 2 randomized strata. OS was defined as the number of months from date of randomization until date of death due to any cause.
The OR was defined as the proportion of participants achieving certain response on treatment among LCH patients, criteria were defined per protocol. Better response were defined as achieving complete disease resolution (NAD) or disease regression (AD better); intermediate response defined as stable or unchanged disease status; worse response defined as disease progression.
The OR was defined as the proportion of participants achieving certain response on treatment among LCH-related disorder patients, criteria were defined per protocol. A clinical response of progressive metabolic disease (PMD) defined as CT-based target lesion abnormal and bone marrow new or recurrent involvement; partial metabolic response (PMR) defined as CT-based target lesion decreasing or disease regressed.
Percent of patients achieving cytoreductive response of marrow cellularity \<20% and blasts \< 10%
Overall Response: complete remission(CR) or marrow CR or partial remission (PR), or hematologic improvement (HI) in participants with myelodysplastic syndromes (MDS);CR or CR with incomplete count recovery(CRi),or PR in participants with secondary acute myeloid leukemia (sAML). Per International Working Group (IWG) criteria, CR:\<= 5% myeloblasts in bone marrow; persistent dysplasia had to be noted; peripheral blood showing hemoglobin (Hgb)\>=11g/dL, platelets \>=100\*10\^9/L,neutrophils \>=1\*10\^9/L, blasts 0%. Marrow CR:\<=5%myeloblasts in bone marrow and decreased by \>=50% over pretreatment; any HI response in peripheral blood. CRi: meeting all criteria for CR except for residual thrombocytopenia (platelet \<100\*10\^9/L) or neutropenia (ANC \<1.0\*10\^9/L). PR: all CR criteria if abnormal before treatment except that marrow blasts should have decreased by \>=50% over pretreatment but still \>5%. HI: meeting any of the erythroid, platelet, or neutrophil improvement categories for at least 8 weeks.
Best response was assessed by the Independent Response Review Panel(IRRP) after two cycles of treatment. Overall remission(OR) is the sum of complete remission(CR) and complete remission in the absence of platelet recovery(CRp). CR includes normal values for peripheral blood cell counts (absolute neutrophil and platelet) and leukemic blast cells from bone marrow biopsy or aspirate, and absence of extramedullary disease. Partial remission(PR) includes recovery of peripheral blood cells with improved but still abnormal values in leukemic blast cells.
ORR rate was defined as the sum of the number of participants in the study population with complete remission (CR), complete remission with incomplete blood count recovery (CRi), or partial remission (PR) divided by the total number of participants in the study population. ORR rate was determined by assessment of morphology and blast count from bone marrow aspirates and peripheral blood performed prior to first dose and at the end of clofarabine treatment. The ORR was determined at the end of each cycle of clofarabine, and assessed using the participant's best response to clofarabine treatment.
Response assessed by blood test or bone marrow aspirate following day 21 of induction and then every 2 weeks thereafter until remission or non-response. Complete remission (CR): Disappearance all clinical and/or radiologic evidence of disease; Neutrophil count \> 1.0 x10\^9/L and platelet count \>100x10\^9/L, and normal bone marrow differential (\< 5% blasts). Complete remission without platelet recovery (CRp): Peripheral blood and bone marrow results as for CR, but with platelet counts of \> 20 x 10\^9/L and \< 100 x 10\^9/L. Partial remission (PR): Peripheral blood count recovery as for CR, but with decrease in marrow blasts of \> 50% and not more than 6-25% abnormal cells in the marrow. All other responses considered as failures.
Maximum Tolerated Dose for Clofarabine. Cohorts of 3 patients each will receive doses of clofarabine increased in increments as follows: 4, 6, 8, 10, 12,…etc mg/m2/day for 5 days. The dose level immediately below the MTD will be used to treat patients in the Phase II part of the study. Starting dose of 4 mg/m2.
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused \<= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m\^2, etoposide 100 mg/m\^2 and cyclophosphamide 440 mg/m\^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD.
The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort.
Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with \<5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 \[x 10\^9/L\] 2) CR in absence of plt recovery (CRp): plt ≥20 to \<75 x 10\^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with \<5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.
| Arm | Type | Description |
|---|---|---|
| clofarabine (IV formulation) and cytarabine | EXPERIMENTAL | Participants received clofarabine (40 mg/m\^2) administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m\^2 administered as a 2-hour infusion. Participants could receive up to 3 cycles of treatment (induction, re-induction, and consolidation) Complete induction cycle = 5 consecutive days of treatment Re-induction cycle = 5 consecutive days of treatment at the original or modified dose Consolidation cycle = 4 consecutive days of treatment at the original or modified dose |
| placebo and cytarabine | EXPERIMENTAL | Participants received placebo administered as a 1-hour infusion followed 3 hours later (from end of infusion) by cytarabine 1 g/m\^2 administered as a 2-hour infusion. Patients could receive up to 3 cycles of treatment (induction, re-induction, and consolidation) |
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | EXPERIMENTAL | Participants with recurrent or refractory LCH defined as with multi-focal or multi-system disease who have recurred (or have refractory disease) after at least one prior systemic chemotherapy regimen. Patient will receive Clofarabine administered via IV on days 1-5, 25 mg/m2/day per cycle for 2 cycles. At the end of cycle 2 if no disease progression, will continue with same dose for maintenance treatment for 4 additional cycles. |
| LCH-related disorders + Clofarabine | EXPERIMENTAL | Participants with LCH-related disorders defined as who require systemic chemotherapy including participants with Rosai Dorfman Disease (RDD) who have not responded to or recurred after treatment with corticosteroids. Erdheim Chester Disease (ECD) subjects who have confirmed presence of BRAF V600E mutation must have not responded to, have recurred after, or be unable to receive treatment with a BRAF inhibitor. Patient will receive Clofarabine administered via IV on days 1-5, 25 mg/m2/day per cycle for 2 cycles. At the end of cycle 2 if no disease progression, will continue with same dose for maintenance treatment for 4 additional cycles. |
| Clofarabine | EXPERIMENTAL | Clofarabine 30 mg/m2/day IV infusion over one hour for 5 consecutive days |
| Clofarabine 55 mg/day | EXPERIMENTAL | Participants received Clofarabine 55 mg/day orally for 5 consecutive days of each 28-day treatment cycle until disease progression or death, whichever comes first (maximum study duration: up to 4 years). |
| Clofarabine 35 mg/day | EXPERIMENTAL | Participants received Clofarabine 35 mg/day orally for 5 consecutive days of each 28-day treatment cycle until disease progression or death, whichever comes first (maximum study duration: up to 4 years). |
| Clofarabine 25 mg/day | EXPERIMENTAL | Participants received Clofarabine 25 mg/day orally for 5 consecutive days of each 28-day treatment cycle until disease progression or death, whichever comes first (maximum study duration: up to 4 years). |
| Clofarabine with Busulfan | EXPERIMENTAL | Clofarabine 40 mg/m2 IV QD × 5 days Busulfan (Busulfex™) 3.2 mg/kg IV QD × 2 days |
| Clofarabine + Ara-C | EXPERIMENTAL | Clofarabine 40 mg/m\^2 by vein over 1 hour daily for 5 days. Ara-C Starting dose: 1 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. |
| Clofarabine + Idarubicin | EXPERIMENTAL | Clofarabine 22.5 mg/m\^2 by vein over 1 hour daily for 5 days. Idarubicin 10 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. |
| Clofarabine + Idarubicin + Ara-C | EXPERIMENTAL | Clofarabine 22.5 mg/m\^2 by vein over 1 hour daily for 5 days. Idarubicin 6 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. Ara-C Starting dose: 0.75 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. |
| 1 | EXPERIMENTAL | Clofarabine 4 mg/m\^2 days 1-5 of every cycle for a maximum of 6 cycles. |
| clofarabine, etoposide, cyclophosphamide | EXPERIMENTAL | Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m\^2, etoposide dosage from 75-100 mg/m\^2, cyclophosphamide dosage from 340-440 mg/m\^2. Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m\^2, etoposide 100 mg/m\^2 and cyclophosphamide 440 mg/m\^2 delivered intravenously |
| Name | Type | Description |
|---|---|---|
| clofarabine (IV formulation) | DRUG | clofarabine (IV formulation) infusion 40mg/m\^2 / day up to 3 cycles |
| placebo | DRUG | placebo (sodium Chloride) 1-hour IV infusion |
| cytarabine | DRUG | cytarabine IV infusion 1g/m\^2/day for up to 3 cycles |
| Clofarabine | DRUG | second-generation purine nucleoside analog |
| Clofarabine with Busulfan | DRUG | Clofarabine 40 mg/m2 IV QD × 5 days Busulfan (Busulfex™) 3.2 mg/kg IV QD × 2 days |
| Clofarabine 40mg/m^2 | DRUG | 40 mg/m\^2 by vein over 1 hour daily for 5 days. |
| Idarubicin 10mg/m^2 | DRUG | 10 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. Clofarabine + Idarubicin plus Ara-C: 6 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. |
| Ara-C 0.75 g/m^2 | DRUG | 0.75 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. |
| Clofarabine 22.5mg/m^2 | DRUG | 22.5 mg/m\^2 by vein over 1 hour daily for 5 days. |
| Ara-C 1 g/m^2 | DRUG | 1 g/m\^2 by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. |
| Idarubicin 6 mg/m^2 | DRUG | 6 mg/m\^2 by vein over 30 minutes, around one hour after clofarabine, for the first 3 days of 5 day cycle. |
| Ara-C | DRUG | - |
| Etoposide | DRUG | Etoposide 75-100 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle following clofarabine therapy. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods. |
| Cyclophosphamide | DRUG | Cyclophosphamide 340-440 mg/m²/day as 30-60 minute intravenous (IV) infusion daily for 5 days of a 28 day cycle following the other two interventions. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods. |
| clofarabine (oral formulation) | DRUG | Cohorts of 3 patients each were to receive oral clofarabine administered daily for 5 days followed by 23 days of rest (1 cycle) and repeated every 28 days depending on toxicity and response. The starting dose of clofarabine was to be 1 mg/m2/day with subsequent dose escalation to occur in increments of 50% for the first 5 dose levels (1.5, 2.25, 3.5, and 5.0 mg/m2/day) and in increments of 25% thereafter until the MTD/RP2D was determined. |
Inclusion Criteria: * Have a diagnosis of Acute Myelogenous Leukemia (AML) according to World Health Organization (WHO) classification * Relapsed after receiving up to 2 prior induction regimens (i.e. first or second relapse)or are refractory to not more than one prior combination chemotherapy indu...
Clofarabine is a small molecule oncology drug studied in hematologic malignancies, including acute lymphoblastic leukemia, acute myelogenous leukemia, acute myeloid leukemia, B-cell lymphoma, and Langerhans cell histiocytosis. It is being evaluated in both pediatric and adult patient populations across these blood cancers and related disorders.
Clofarabine targets DNA polymerases, specifically POLA1, POLD1, POLD2, POLD3, POLD4, and POLE. It acts as an inhibitor of these enzymes, which are involved in DNA replication and repair. This mechanism underlies its activity in hematologic malignancies.
Clofarabine is developed by Sanofi, which trades under the ticker SNY. Sanofi is the company responsible for the clinical development of the drug across its studied indications in oncology.
Clofarabine is in Phase 2 clinical development. It is an investigational small molecule and has been studied in four clinical trials, with one trial currently active and not recruiting. The completed trials include Phase 1 and Phase 2 studies.
Clofarabine has been studied in trials including NCT02425904 in Langerhans cell histiocytosis, NCT01196013 in Japanese pediatric patients with relapsed or refractory acute lymphoblastic leukemia, NCT01090167 in Japanese patients with acute myeloid leukemia, and NCT00930098 in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.