TREATMENT OF LEUKEMIAS AND LYMPHOMAS WITH COMBINATIONS OF BCL-2 INHIBITORS AND PLK1 INHIBITORS
Provided include methods, compositions and kits for treating a leukemia or lymphoma in a subject. The method can comprise administrating a BCL-2 inhibitor and a PLK1 inhibitor (for example, onvansertib) to the subject in a manner sufficient to inhibit progression of the leukemia or lymphoma.
1 . A method of treating leukemia or lymphoma, the method comprising: administrating a B-cell lymphoma 2 (BCL-2) inhibitor and a Polo-like kinase 1 (PLK1) inhibitor to a subject with leukemia or lymphoma, thereby inhibiting progression of the leukemia or lymphoma.
2 . The method of claim 1 , wherein the subject has leukemia or lymphoma.
3 . The method of claim 2 , wherein the leukemia is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphocytic leukemia, or chronic myelomonocytic leukemia (CMML), and/or wherein the lymphoma is a Hodgkin lymphoma or a Non-Hodgkin lymphoma.
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8 . The method of claim 1 , wherein the leukemia or the lymphoma is advanced, metastatic, refractory, and/or relapsed.
9 . The method of claim 1 , wherein the PLK inhibitor and the BCL-2 are co-administered simultaneously or administered sequentially.
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11 . The method of claim 1 , wherein the administration of the PLK1 inhibitor, the BCL-2 inhibitor, or both is oral administration.
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13 . The method of claim 1 , wherein the inhibition of the leukemia or lymphoma progression is greater than the combined inhibition of progression caused by the BCL-2 inhibitor alone plus the PLK1 inhibitor alone.
14 . The method of claim 1 , wherein the subject achieves a complete response.
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18 . The method of claim 1 , wherein the BCL-2 inhibitor and the PLK1 inhibitor are each administered to the subject in a cycle of at least twice within a week.
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20 . The method of claim 1 , wherein the BCL-2 inhibitor, the PLK1 inhibitor, or both are administered in a cycle of at least 7 days.
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23 . The method of claim 20 , wherein the PLK1 inhibitor is administered on at least four days in the cycle.
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25 . The method of claim 1 , wherein the BCL-2 inhibitor is administered daily.
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28 . The method of claim 1 , wherein the BCL-2 inhibitor is venetoclax, obatoclax, HA14-1, navitoclax, ABT-737, TW-37, AT101, sabutoclax or gambogic acid.
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32 . The method of claim 1 , wherein the PLK1 inhibitor is onvansertib, BI2536, Volasertib (BI 6727), GSK461364, AZD1775, CYC140, HMN-176, HMN-214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960 or Ro3280.
33 . The method of claim 1 , wherein the PLK1 inhibitor is onvansertib.
34 . The method of claim 33 , wherein onvansertib is administered at 12 mg/m 2 -90 mg/m 2 .
35 . The method of claim 33 , wherein the concentration of onvansertib in a blood of the subject satisfies at least one of the criteria:
(i) a maximum concentration (C max ) of onvansertib in the blood of the subject is from about 100 nmol/L to about 1500 nmol/L,
(ii) an area under curve (AUC) of a plot of the concentration of onvanserib in the blood of the subject over time is from about 1000 nmol/L.hour to about 400000 nmol/L.hour,
(iii) a time (T max ) to reach the maximum concentration of onvansertib in the blood of the subject is from about 1 hour to about 5 hours, and/or
(iv) an elimination half-life (T 1/2 ) of onvansertib in the blood of the subject is from about 10 hours to about 60 hours.
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44 . The method of claim 1 , further comprising determining leukemia or lymphoma status of the subject and/or responsiveness of the subject to a PLK1 inhibitor treatment.
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48 . A kit comprising: a Polo-like kinase 1 (PLK1) inhibitor; and a manual providing instructions for co-administrating the PLK1 inhibitor with a B-cell lymphoma 2 (BCL-2) inhibitor to a subject for treating leukemia and lymphoma.
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85 . The kit of claim 48 , further comprising the BCL-2 inhibitor.