COMBINATIONS OF CD33 ANTIBODY DRUG CONJUGATES WITH HYPOMETHYLATING AGENTS

Abstract

This invention relates to treatment of cancer using a CD33 antibody drug conjugate in combination with hypomethylating agents.

Claims

1. A method of treating CD33 expressing acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering a hypomethylating agent and 10 g/kg of a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent, and wherein the hypomethylating agent is selected from the group consisting of 5-azacytidine and 5-aza-2-deoxycytidine.

2. The method of claim 1, wherein the PBD cytotoxic agent has the formula ##STR00007##

3. The method of claim 1, wherein the hypomethylating agent is 5-azacytidine.

4. The method of claim 3, wherein the 5-azacytidine is administered at a concentration between 50-100 mg/m.sup.2.

5. The method of claim 3, wherein the 5-azacytidine is administered at a concentration of about 75 mg/m.sup.2.

6. The method of claim 4, wherein the 5-azacytidine is administered at a concentration of 75 mg/m.sup.2.

7. The method of claim 1, wherein the hypomethylating agent is 5-aza-2-deoxycytidine.

8. The method of claim 7, wherein the 5-aza-2-deoxycytidine is administered at a concentration between 15-25 mg/m.sup.2.

9. The method of claim 7, wherein the 5-aza-2-deoxycytidine is administered at a concentration of about 20 mg/m.sup.2.

10. The method of claim 7, wherein the 5-aza-2-deoxycytidine is administered at a concentration of 20 mg/m.sup.2.

11. The method of claim 1, wherein the subject is 75 years or older.

12. A method of treating CD33-expressing secondary acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering a hypomethylating agent and between 20-40 g/kg of a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent, and wherein the hypomethylating agent is 5-aza-2-deoxycytidine.

13. The method of claim 12, wherein the PBD cytotoxic agent has the formula ##STR00008##

14. The method of claim 12, wherein the 5-aza-2-deoxycytidine is administered at a concentration of about 20 mg/m.sup.2.

15. The method of claim 12, wherein the 5-aza-2-deoxycytidine is administered at a concentration of 20 mg/m.sup.2.

16. The method of claim 12, wherein the 5-aza-2-deoxycytidine is administered at a concentration of about 20 mg/m.sup.2.

17. The method of claim 12, wherein the CD33-ADC is administered at 20 g/kg.

18. The method of claim 12, wherein the CD33-ADC is administered at 30 g/kg.

19. The method of claim 12, wherein the CD33-ADC is administered at 40 g/kg.

20. The method of claim 12, wherein the subject is younger than 75 years old.

21. A method of treating CD33-expressing relapsed or refractory acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering a hypomethylating agent and between 20-40 g/kg of a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent, and wherein the hypomethylating agent is 5-aza-2-deoxycytidine.

22. The method of claim 21, wherein the PBD cytotoxic agent has the formula ##STR00009##

23. The method of claim 21, wherein the 5-aza-2-deoxycytidine is administered at a concentration of about 20 mg/m.sup.2.

24. The method of claim 21, wherein the 5-aza-2-deoxycytidine is administered at a concentration of 20 mg/m.sup.2.

25. The method of claim 21, wherein the 5-aza-2-deoxycytidine is administered at a concentration of about 20 mg/m.sup.2.

26. The method of claim 21, wherein the CD33-ADC is administered at 20 g/kg.

27. The method of claim 21, wherein the CD33-ADC is administered at 30 g/kg.

28. The method of claim 21, wherein the CD33-ADC is administered at 40 g/kg.

29. The method of claim 21, wherein the subject is younger than 75 years old.

Description

DETAILED DESCRIPTION

[0054] This invention demonstrates optimal dosing of SGN-CD33 A, a CD33-antibody drug conjugate (CD33-ADC), i.e., h2H12 antibody conjugated to a PBD, with the hypomethylating agents 5-azacytidine or 5-aza-2-deoxycytidine.

[0055] I. CD33 Antibody Drug Conjugates

[0056] A. Anti-CD33 Antibodies

[0057] The anti-CD33 antibody disclosed herein is the humanized 2H12 antibody (h2H12). The murine 2H12 antibody was raised in mice, using the human CD33 protein as an immunogen. After making hybridomas from the spleens of the immunized mice, followed by screening for CD33 binding activity, the murine 2H12 antibody was selected for humanization. The h2H12 antibody was derived from the murine 2H12 antibody. The humanization procedure is disclosed in PCT publication WO 2013/173,496; which is herein incorporated by reference for all purposes. The variable region sequences of the h2H12 light and heavy chains are provided as SEQ ID NO:1 and SEQ ID NO:2, respectively.

[0058] The h2H12 antibody comprises human constant regions. Sequences of human constant regions are provided in the sequence listing. The heavy chain constant region of h2H12 includes a substitution mutation, S239C, to facilitate conjugation of a drug-linker to the antibody. The sequence of a human constant region comprising the S239C mutation is provided at SEQ ID NOs:6 and 7. The h2H12 antibody comprising the S239C mutation is also referred to as h2H12EC.

[0059] B. Drug Linkers

[0060] Exemplary CD33 antibody-drug conjugates include PBD based antibody-drug conjugates; i.e., antibody-drug conjugates wherein the drug component is a PBD drug.

[0061] PBDs are of the general structure:

##STR00003##

They differ in the number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (NC), a carbinolamine (NHCH(OH)), or a carbinolamine methyl ether (NHCH(OMe)) at the N10-C11 position, which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral C11a position which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In Antibiotics III. Springer-Verlag, New York, pp. 3-11 (1975); Hurley and Needham-VanDevanter, Acc. Chem. Res., 19, 230-237 (1986)). The ability of PBDs to form an adduct in the minor groove enables them to interfere with DNA processing, hence their use as antitumour agents.

[0062] The biological activity of these molecules can be potentiated by joining two PBD units together through their C8/C-hydroxyl functionalities via a flexible alkylene linker (Bose, D. S., et al., J. Am. Chem. Soc., 114, 4939-4941 (1992); Thurston, D. E., et al., J. Org. Chem., 61, 8141-8147 (1996)). The PBD dimers are thought to form sequence-selective DNA lesions such as the palindromic 5-Pu-GATC-Py-3 interstrand cross-link (Smellie, M., et al., Biochemistry, 42, 8232-8239 (2003); Martin, C., et al., Biochemistry, 44, 4135-4147) which is thought to be mainly responsible for their biological activity.

[0063] In some embodiments, PBD based antibody-drug conjugates comprise a PBD dimer linked to an anti-CD33 antibody. The monomers that form the PBD dimer can be the same or different, i.e., symmetrical or unsymmetrical. The PBD dimer can be linked to the anti-CD33 antibody at any position suitable for conjugation to a linker. For example, in some embodiments, the PBD dimer will have a substituent at the C2 position that provides an anchor for linking the compound to the anti-CD33 antibody. In alternative embodiments, the N10 position of the PBD dimer will provide the anchor for linking the compound to the anti-CD33 antibody.

[0064] Typically the PBD based antibody-drug conjugate comprises a linker between the PBD drug and the anti-CD33 antibody. The linker may comprise a cleavable unit (e.g., an amino acid or a contiguous sequence of amino acids that is a target substrate for an enzyme) or a non-cleavable linker (e.g., linker released by degradation of the antibody). The linker may further comprise a maleimide group for linkage to the antibody, e.g., maleimidocaproyl. The linker may, in some embodiments, further comprise a self-immolative group, such as, for example, a p-aminobenzyl alcohol (PAB) unit.

[0065] An exemplary PBD for use as a conjugate is described in International Application No. WO 2011/130613 and is as follows wherein the wavy line indicates the site of attachment to the linker:

##STR00004##

or a pharmaceutically acceptable salt thereof. An exemplary linker is as follows wherein the wavy line indicates the site of attachment to the drug and the antibody is linked via the maleimide group.

##STR00005##

[0066] Exemplary PBDs based antibody-drug conjugates include antibody-drug conjugates as shown below wherein Ab is an antibody as described herein:

##STR00006##

or a pharmaceutically acceptable salt thereof. The drug loading is represented by p, the number of drug-linker molecules per antibody. Depending on the context, p can represent the average number of drug-linker molecules per antibody, also referred to the average drug loading. The variable p ranges from 1 to 20 and is preferably from 1 to 8. In some preferred embodiments, when p represents the average drug loading, p ranges from about 2 to about 5. In some embodiments, p is about 2, about 3, about 4, or about 5. In some aspects, the antibody is conjugated to the drug linker via a sulfur atom of a cysteine residue that is engineered into the antibody. In some aspects, the cysteine residue is engineered into the antibody at position 239 (IgG1) as determined by the EU index (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991).

[0067] C. CD33-ADCs

[0068] As used herein a CD33-ADC refers to an ADC that comprises an h2H12 antibody conjugated to a PBD molecule. The antibody portion comprises the variable light chain region of SEQ ID NO:1 and the variable heavy chain region of SEQ ID NO:2. The constant region is a human IgG1 constant region. The heavy chain constant region has a substitution mutation at amino acid 239 using Kabat numbering, i.e., S239C. The cysteine residue at position 239 is the point of attachment for the PBD molecule. The structure of the antibody, the linker and the PBD molecule is shown above. Methods to make the CD33-ADC are disclosed in PCT publication WO 2013/173,496 and PCT publication WO 2011/130613, both of which are incorporated by reference for all purposes.

[0069] II. Hypomethylating Agents

[0070] Hypomethylating agents inhibit DNA methylation by inhibiting the activity of the DNA methyltransferases. Exemplary hypomethylating agents are 5-azacytidine (VIDAZA) and 5-aza-2-deoxycytidine or decitabine (DACOGEN). Both compounds are cytidine analogs, approved drugs, and are commercially available. 5-azacytidine is incorporated in to both DNA and RNA. See, e.g., Raj and Mufti Thera. and Clin. Risk Manag. 2:377 (2006). Once in DNA, it binds irreversibly to DNA methyltransferases, thereby blocking DNA methylation. Decitabine is incorporated only into DNA, but acts through a similar mechanism. See, e.g., ibid.

[0071] III. Treatment of Acute Myeloid Leukemia (AML)

[0072] CD33-ADCs in combination with hypomethylating agents can be used to treat acute myeloid leukemia (AML), preferably AML that has detectable levels of CD33 measured at either the protein (e.g., by immunoassay using one of the exemplified antibodies) or mRNA level. Some such AML cells show elevated levels of CD33 relative to noncancerous tissue of the same type, preferably from the same patient. An exemplary level of CD33 on AML samples amenable to treatment is 5000-150000 CD33 molecules per cell, although higher or lower levels can be treated. Optionally, a level of CD33 in a cancer is measured before performing treatment.

[0073] The combination of CD33-ADC with a hypomethylating agent treatment can be applied to patients who are treatment nave, who are refractory to conventional treatments (e.g., chemotherapy or MYLOTARG (gemtuzumab ozogamicin), or who have relapsed following a response to such treatments. Some cancer cells develop resistance to a therapeutic agent after increasing expression of a protein increases efflux of the therapeutic agent out of the cancer cell. Such proteins include P-glycoprotein, multidrug resistance-associated protein, lung resistance-related protein, and breast cancer resistance protein. Detection of drug resistance in cancer cells can be performed by those of skill. Antibodies or assays that detect efflux proteins are commercially available from, e.g., Promega, Millipore, Abcam, and Sigma-Aldrich. In one embodiment, a CD33-ADC in combination with a hypomethylating agent is used to treat a subject with a multi-drug resistant, CD33-positive AML.

[0074] In some embodiments the combination of a CD33-ADC with a hypomethylating agent is used to treat elderly patients, e.g., patients 60 years old or older who have CD33 positive AML. In other embodiments the combination of a CD33-ADC with a hypomethylating agent is used to treat elderly patients, e.g., patients 75 years old or older who have CD33 positive AML. In further embodiments the combination of a CD33-ADC with a hypomethylating agent is used to treat elderly patients, e.g., patients 75-100 years old who have CD33 positive AML, patients 75-90 years old who have CD33 positive AML, or patients 75-85 years old who have CD33 positive AML. Other frail or unfit patients can be treated using the combination of a CD33-ADC and a hypomethylating agent, for example, patients that decline or who are not candidates for standard induction/consolidation treatment. Additionally, elderly patients with poor risk disease characteristics can also be treated using the combination, given the lack of benefit observed with intensive chemotherapy. Poor disease risk characteristics are known and described at, e.g., Hou et al., Leukemia 28:50-58 (2014).

[0075] In another embodiment, the combination of a CD33-ADC with a hypomethylating agent is used to treat fit, non-elderly patients, i.e., patients younger than 75 years old who have difficult to treat forms of AML. Difficult to treat forms of AML include, e.g., relapsed or refractory AML or secondary AML. Secondary AML is associated with exposure to a leukemogenic agent, e.g., previous chemotherapy or radiotherapy, some immunosuppressive drugs or environmental leukemogenic agents).

[0076] IV. Dosage and Administration

[0077] Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration). Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries. The formulation depends on the route of administration chosen. For injection, antibodies can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline or acetate buffer (to reduce discomfort at the site of injection). The solution can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively antibodies can be in lyophilized form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Formulations for the CD33-ADC comprising h2H12 antibody and a PBD molecule are disclosed e.g., at PCT/US2014/024466.

[0078] The CD33-ADC is administered intravenously, as is decitabine. 5-Azacytidine can be administered intravenously or subcutaneously.

[0079] The CD33-ADC can be combined with a hypomethylating agent concurrently or sequentially for treatment of a CD33-expressing cancer or disorder, e.g., AML or a myelodysplastic syndrome, at the discretion of the treating physician.

[0080] In one embodiment, the combination of the CD33-ADC with 5-azacytidine is dosed on a twenty-eight day schedule. 5-azacytidine is administered on days 1-7 or on days 1-5, followed by two days off, and two more days of 5-azacytidine. In one embodiment, 10 g/kg CD33-ADC is administered on the final day of 5-azacytidine treatment. After day 28, the cycle is repeated, with the total number of cycles determined by the physician.

[0081] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule. Decitabine is administered on days 1-5. In one embodiment, 10 g/kg CD33-ADC is administered on the final day of decitabine treatment, e.g., day 5. After day 28, the cycle is repeated, with the total number of cycles determined by the physician.

[0082] The CD33-ADC can be administered in combination with 5-azacytidine or decitabine in the following dose ranges: about 10 g/kg CD33-ADC in combination with 5-azacytidine or decitabine. In another embodiment, the CD33-ADC is administered at 10 g/kg in combination with 5-azacytidine or decitabine.

[0083] 5-Azacytidine can be administered in the following dose ranges in combination with the CD33-ADC: 10-200 mg/m.sup.2, 25-150 mg/m.sup.2, or 50-100 mg/m.sup.2. In some embodiments, 5-azacytidine is administered at about 75 mg/m.sup.2 in combination with the CD33-ADC. In another embodiment, 5-azacytidine is administered at 75 mg/m.sup.2 in combination with the CD33-ADC. Decitabine can be administered in the following dose ranges in combination with the CD33-ADC: 5-50 mg/m.sup.2, 10-30 mg/m.sup.2, or 15-25 mg/m.sup.2. In some embodiments, decitabine is administered at about 20 mg/m.sup.2 in combination with the CD33-ADC. In another embodiment, decitabine is administered at 20 mg/m.sup.2 in combination with the CD33-ADC.

[0084] In one embodiment, the combination of the CD33-ADC with 5-azacytidine is dosed on a twenty-eight day schedule. 5-azacytidine is administered at 75 mg/m.sup.2 on days 1-7 or on days 1-5, followed by two days off, and two more days of 5-azacytidine at 75 mg/m.sup.2. The CD33-ADC is administered at about 10 g/kg on the final day of 5-azacytidine treatment. After day 28, the cycle is repeated, with the total number of cycles determined by the physician.

[0085] In one embodiment, the combination of the CD33-ADC with 5-azacytidine is dosed on a twenty-eight day schedule. 5-azacytidine is administered at 75 mg/m.sup.2 on days 1-7 or on days 1-5, followed by two days off, and two more days of 5-azacytidine at 75 mg/m.sup.2. The CD33-ADC is administered at 10 g/kg on the final day of 5-azacytidine treatment. After day 28, the cycle is repeated, with the total number of cycles determined by the physician.

[0086] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at about 10 g/kg on the final day of decitabine treatment, e.g., day 5. After day twenty-eight, the cycle is repeated, with the total number of cycles determined by the physician.

[0087] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. After day twenty-eight, the cycle is repeated, with the total number of cycles determined by the physician.

[0088] In one embodiment, the combination of the CD33-ADC with 5-azacytidine is dosed on a twenty-eight day schedule for a patient with CD33 positive AML who is 75 years old or older. 5-azacytidine is administered at 75 mg/m.sup.2 on days 1-7 or on days 1-5, followed by two days off, and two more days of 5-azacytidine at 75 mg/m.sup.2. The CD33-ADC is administered at about 10 g/kg on the final day of 5-azacytidine treatment. After day 28, the cycle is repeated, with the total number of cycles determined by the physician.

[0089] In one embodiment, the combination of the CD33-ADC with 5-azacytidine is dosed on a twenty-eight day schedule for a patient with CD33 positive AML who is 75 years old or older. 5-azacytidine is administered at 75 mg/m.sup.2 on days 1-7 or on days 1-5, followed by two days off, and two more days of 5-azacytidine at 75 mg/m.sup.2. The CD33-ADC is administered at 10 g/kg on the final day of 5-azacytidine treatment. After day 28, the cycle is repeated, with the total number of cycles determined by the physician.

[0090] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive AML who is 75 years old or older. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at about 10 g/kg on the final day of decitabine treatment, e.g., day 5. After day twenty-eight, the cycle is repeated, with the total number of cycles determined by the physician.

[0091] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive AML who is 75 years old or older. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. After day twenty-eight, the cycle is repeated, with the total number of cycles determined by the physician.

[0092] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive secondary AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at between 20-40 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0093] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive secondary AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 20 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0094] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive secondary AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 30 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0095] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive secondary AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 40 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0096] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive relapsed/refractory AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at between 20-40 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0097] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive relapsed/refractory AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 20 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0098] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive relapsed/refractory AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 30 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

[0099] In one embodiment, combination of the CD33-ADC with decitabine is dosed on a twenty-eight day schedule for a patient with CD33 positive relapsed/refractory AML who is younger than 75 years old. Decitabine is administered at 20 mg/m.sup.2 on days 1-5. The CD33-ADC is administered at 40 g/kg on the final day of decitabine treatment, e.g., day 5. This dose cycle is repeated for up to 4 cycles. At cycle five, the CD33-ADC is administered at 10 g/kg on the final day of decitabine treatment, e.g., day 5. Cycle 5 dosing is repeated, with the total number of cycles determined by the physician.

EXAMPLES

[0100] The following examples are offered to illustrate, but not to limit the claimed invention.

Example 1: CD33-ADC in Combination with Hypomethylating Agents is Well Tolerated and Elicits a High Remission Rate in Older Patients with AML

Methods

[0101] A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-leukemic activity of 33 A in combination with an HMA. Eligible patients (ECOG 0-1) must have previously untreated CD33-positive AML, and have declined intensive therapy. A single dose level of 33 A, 10 mcg/kg, was administered outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5 day regimen], standard dosing). Patients with clinical benefit may continue treatment until relapse or unacceptable toxicity. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of 100,000/L or neutrophils of 1,000/L (Cheson 2003).

Results

[0102] To date, 24 patients (63% male) with a median age of 77 years (range, 66-83) have been treated with the combination therapy. 42% of patients had adverse cytogenetics (MRC), 23 patients were treatment nave and 1 patient had received prior low intensity therapy for myelodysplastic syndrome (MDS). At baseline, patients had a median of 60% BM blasts (range, 2%-90%) and a median of WBC of 2.2 (range, 1-132). At the time of this interim analysis, patients were on treatment for a median of 13.5+ weeks with 17 patients continuing treatment; no DLTs have been reported. Grade 3 or higher adverse events (AE) reported in >20% of patients were fatigue (54%), febrile neutropenia (46%), anemia (25%), neutropenia (25%), and thrombocytopenia (21%). Other treatment-emergent AEs regardless of relationship to study treatment reported in >20% of patients were nausea (29%), decreased appetite (25%), and constipation (21%). Thirty- and 60-day mortality rates are 0% and 4% respectively with no treatment-related deaths reported. Fifteen of the 23 efficacy evaluable patients (65%) achieved CR (5) or CRi (10). Remissions were generally obtained after 2 cycles of treatment and were observed in many patients with adverse risk including underlying myelodysplasia (6/8, 75%) and adverse cytogenetics (8/9, 89%). Median OS has not been reached with 20 patients alive at the time of this data cut.

[0103] The combination of 33 A with HMA appears to be well-tolerated, active, and has no identified off-target toxicities. Activity with the combination compares favorably with historical experience with HMAs alone in this patient population.

[0104] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.