Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia

Phase 1b Key Inclusion Criteria:

1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at thetime of study treatment initiation.

2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in thebone marrow (M2 or M3 disease), with or without extramedullary disease.

-To be eligible, subjects must have had 1 or more prior therapeutic attempts,defined as:

• Early first relapse (< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis afterachieving a CR (T-ALL)

• First refractory bone marrow relapse occurring any time after originaldiagnosis after achieving a CR (ie, ≥1 failed attempt to induce a secondremission) OR

• Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR

• Failing to achieve a CR from original diagnosis after at least 1 inductionattempt

3. Subjects must have fully recovered from the acute toxic effects of all previouschemotherapy, immunotherapy, or radiotherapy treatment before enrollment.

4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upperlimit of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN,the subject must have a calculated creatinine clearance or radioisotope glomerularfiltration rate (GFR) ≥ 70 mL/min/1.73 m2.

5. Adequate liver function, defined as both of the following:

• Total bilirubin ≤ 1.5 × institutional ULN except in the presence of GilbertSyndrome

• Alanine aminotransferase (ALT) ≤ 5 × institutional ULN

6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively.

Phase 2 Inclusion Criteria:

1. Subject's legally acceptable representative has provided informed consent when thesubject is legally too young to provide informed consent and the subject hasprovided written assent based on local regulations and/or guidelines prior to anystudy-specific activities/procedures being initiated, except for standard of carelocal testing as permitted per protocol.

2. Age greater than or equal to 1 month to less than 21 years. Subjects greater than orequal to 18 years must have had their original diagnosis at less than 18 years ofage.

3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.

4. Subjects must have a documented first remission, less than 5% blasts in the bonemarrow (M1 bone marrow) and no evidence of extramedullary disease.

5. T-cell ALL with bone marrow relapse (defined as greater than or equal to 5% leukemiablasts in bone marrow) or refractory relapse with or without extramedullary disease. OR B-cell ALL bone marrow relapse or refractory relapse (defined as greater than orequal to 5% leukemia blasts in bone marrow) after having received a targeted B-cellimmune therapy (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or withoutextramedullary disease..

6. Adequate liver function: bilirubin less than or equal to 1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN.

7. Adequate renal function: serum creatinine less than or equal to 1.5 x ULN orglomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m^2; or forchildren less than 2 years of age, greater than or equal to 50 mL/min/1.73 m^2.

8. Adequate cardiac function: shortening fraction greater than or equal to 30% orejection fraction greater than or equal to 50%.

9. Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 12months to less than 16 years of age) performance status greater than or equal to 50%.

10. Subjects must have fully recovered from the acute toxic effects of all previouschemotherapy, immunotherapy, or radiotherapy treatment before enrollment (forexample: recovery from gastrointestinal toxicity may occur more rapidly than lessreversible organ toxicities such as sinusoidal obstruction syndrome ornon-infectious pneumonitis, for serious prior toxicities recommended discussion withAmgen medical monitor).

11. Life expectancy of greater than 6 weeks per investigator's judgement at time ofscreening.

Phase 1b Key Exclusion Criteria:

1. Known allergy to any of the drugs used in the study (Subjects who have had aprevious allergy to PEG-asparaginase and if able, may receive Erwinia asparaginaseat the investigator's discretion)

2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)

3. Left ventricular fractional shortening < 30%

4. History of ≥ Grade 2 pancreatitis

5. Active graft-versus-host disease requiring systemic treatment

6. Positive culture for or other clinical evidence of infection with bacteria or funguswithin 14 days of the initiation of study treatment

7. Down Syndrome

8. Prior therapy restrictions:

• Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before study treatmentinitiation, or at least 14 days before study treatment initiation, if pegylatedmyeloid growth factors were administered.

• Subjects must have completed any type of active immunotherapy (e.g., tumorvaccines) at least 42 days before study treatment initiation.

• Subjects must have received the last dose of a non-monoclonal antibody biologicagent at least 7 days before study treatment initiation.

• At least 3 antibody half-lives must have elapsed since the last dose ofmonoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab)before subjects may initiate study treatment.

• Subjects must not have received other antineoplastic agents with therapeuticintent, excluding hydroxyurea and antimetabolites administered as part ofmaintenance chemotherapy, within 7 days prior to study treatment initiation.

9. Hepatitis B infection with positive hepatitis B DNA

Phase 2 Exclusion Criteria:

1. Prior treatment with carfilzomib.

2. Intolerance, hypersensitivity, or inability to receive any of the chemotherapycomponents of the VXLD regimen. An exception is allowed for allergy to asparaginaseproducts if Erwinia asparaginase is unable to be administered,

3. Autologous HSCT within 6 weeks prior to start of study treatment.

4. Allogeneic HSCT within 3 months prior to start of study treatment.

5. Active GVHD requiring systemic immune suppression.

6. Less than 30 days from discontinuation of immune suppressive therapy administeredfor the treatment of acute or chronic GVHD.

7. Isolated extramedullary relapse.

8. Positive bacterial or fungal infection within 14 days of enrollment (except fordocumented line infection, line has been removed, and blood culture after lineremoval is negative for 5 days prior to first dose of induction therapy).Antibiotics may be administered for prophylaxis as per institutional standards up toand after enrollment.

9. Subjects with less than 3 antibody half-lives since the last dose of monoclonalantibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36days), prior to first dose of investigational product must be discussed with theAmgen medical monitor and may be allowed to enroll based on extent of disease orevidence of rapidly rising peripheral or bone marrow blast counts.

10. Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines)within 42 days prior to first dose of investigational product. If the Amgen medicalmonitor agrees, an exception may be granted to the 42-day requirement for subjectswith rapidly rising peripheral or bone marrow blast counts.

11. Down's syndrome.

12. Presence of another active cancer.

13. History of grade greater than or equal to 2 pancreatitis within 6 months toscreening.

14. Unresolved toxicities from prior anticancer therapy, defined as not having resolvedto CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteriaapart from alopecia or toxicities from prior anticancer therapy that are consideredirreversible and do not trigger another exclusion criterion (defined as having beenpresent and stable for greater than 4 weeks).

15. Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy)within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheralblood leukemic cell counts is allowed until start of investigational product.

16. Active viral infection, including but not limited to cytomegalovirus (CMV),Hepatitis B infection with positive serum hepatitis surface antigen or hepatitis BDNA, HIV, Hepatitis C with detectable hepatitis C RNA. Subjects who have previouslyreceived a stem cell transplant must be screened for CMV infection, unless bothsubject and donor are known to be CMV negative.

17. Currently receiving treatment in another investigational device or product study, orless than 14 days since ending treatment on another investigational device orproduct study.

18. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) ofgreater than 470 msec.

19. History or evidence of any other clinically significant disorder, condition ordisease (with the exception of those outlined above) that, in the opinion of theinvestigator or Amgen physician, if consulted, would pose a risk to subject safetyor interfere with the study evaluation, procedures or completion.

20. Female subject is pregnant or breastfeeding or planning to become pregnant orbreastfeed during treatment and for an additional 6 months after the last dose ofany study treatment or for 12 months after last dose of cyclophosphamide ifadministered during optional consolidation cycle.

21. Female subjects of childbearing potential unwilling to use 1 highly effective methodof contraception during treatment and for an additional 6 months after the last doseof any study treatment or for 12 months after last dose of cyclophosphamide ifadministered during optional consolidation cycle.

22. Female subjects of childbearing potential with a positive pregnancy test assessed atScreening by a serum or urine pregnancy test.

23. Male subjects with a female partner of childbearing potential who are unwilling topractice sexual abstinence (refrain from heterosexual intercourse) or use a condomwith spermicide during treatment and for an additional 6 months after the last doseof any study treatment, even if they have undergone a successful vasectomy.

24. Male subjects with a pregnant partner who are unwilling to practice abstinence oruse a condom with spermicide during treatment, for duration of pregnancy, and for anadditional 6 months after the last dose of any study treatment.

25. Male subjects unwilling to abstain from donating semen or sperm during treatment andfor an additional 6 months after the last dose of any study treatment.

26. Known allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib;for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals,Inc. website).