Dose-Escalation Study of Pixantrone Monotherapy in Pediatric Patients With Relapsed or Refractory Cancer

Approximately thirty-five eligible patients will receive up to six 28-day cycles of
pixantrone monotherapy, with two additional cycles in patients who continue to benefit from
treatment. Each patient will receive pixantrone administered intravenously on days 1, 8, and
15 of each 28-day cycle. There will be three age cohorts, defined as age cohort 1 (12 to less
than 18 years, plus young adults (ages 18-21 years)), age cohort 2 (5 to less than 12 years),
and age cohort 3 (6 months to less than 5 years). During dose escalation, three patients will
first be accrued to the starting dose level. If no DLTs are identified, that dose level will
be declared to not exceed the MTD and three patients will be accrued to the next higher dose
level. Each subsequent dose-escalation level will be accrued per the DLT/MTD determination
schema above. Planned sequential dose-escalation phase will receive 40 mg/m2, 50 mg/m2, 60
mg/m2 or 70 mg/m2 of pixantrone base (on days 1, 8 and 15), as tolerated, based on DLT
evaluation.Dose escalations will follow a standard 3+3 patient cohort escalation plan. No
patients from Age Cohort 3 will be enrolled until 6 patients from age cohorts 1 and 2
(combined) are evaluable for toxicity. After the MTD has been determined, an expansion phase
will be accrued in order to gain better estimates of the safety, tolerability, and anti-tumor
activity of pixantrone monotherapy in pediatric patients when treated at the MTD. Patients
will be offered 3 years of post-study extension phase follow-up with periodic assessments of
cardiac function parameters.

Inclusion Criteria:

1. Patient and/or guardian have signed an Informed Consent Form and Assent approved by
the Institutional Review Board or Institutional Ethics Committee, as appropriate and
necessary, on a per-age basis

2. Age 6 months to 21 years old (initial qualifying diagnosis must have been made at or
before the age of 18 and the patient must be under the care of a pediatric
hematologist/oncologist)

3. Patient received a diagnosis of lymphoma or any non-hematologic malignancy (except
central nervous system [CNS] tumors) for which the patient is considered relapsed or
refractory. (NOTE: CNS metastases are allowable in patients who are deemed not at risk
for progression during the first 30 days, who are neurologically stable, and, if on
corticosteroids, have been on a stable corticosteroid dose for at least 2 weeks.)
Patients who have >1 malignancy ongoing during screening are not eligible

4. Patient must have one or more of the following treatment statuses:

- Has failed at least 2 prior lines of chemotherapy

- Has no curative chemotherapy treatment option available

- Is not considered a candidate for available chemotherapy treatment options

5. In dose-escalation accrual, patients may have un-measurable disease (such as bone
marrow/bone involvement or diffuse tumors)

6. In dose-escalation accrual, patients may have un-measurable disease in cases where the
standard of care would indicate the need for adjuvant chemotherapy after definitive
surgery or radiation, but for whom no standard chemotherapy options are available

7. In expansion cohort accrual, patients must have disease that is evaluable or
measurable for response and progression per standard criteria for their diagnosis
(Refer to the Appendices: RECIST 1.1 Criteria for Evaluation of Solid Tumors,
Including Neuroblastoma, Appendix 18.4], Evaluation of Neuroblastoma [Appendix 18.6],
and the Lymphoma Staging and Disease Response Criteria [Appendix 18.5])

8. Karnofsky-Lansky performance status (as per age of patient) ≥50 (Appendix 18.1)

9. Patient must have one or more of the following cardiac function measurements by
echocardiogram:

- Left ventricular ejection fraction (LVEF) ≥55%

- Left ventricular shortening fraction (LVSF) ≥27%

10. Hemoglobin ≥8 g/dL (can be post-transfusion)

11. Platelet count ≥75 × 109/L

12. Absolute neutrophil count (ANC) ≥0.75 × 109/L

13. Serum direct/conjugated bilirubin ≤1.5 × upper limit of normal (ULN); patients with
clinically diagnosed Gilbert's syndrome and total bilirubin ≤5 × ULN may be enrolled

14. Aspartate aminotransferase (AST; also called serum glutamic-oxaloacetic transaminase
[SGOT]) and alanine aminotransferase (ALT; also called serum glutamic-pyruvic
transaminase [SGPT]) ≤2.5 × ULN, or ≤5 × ULN if elevation is due to hepatic
involvement by tumor

15. Serum creatinine ≤2 × ULN

16. Patients must meet the following criteria with respect to prior cancer therapy,
radiotherapy, and stem cell transplants:

1. Myelosuppressive chemotherapy: At least 3 weeks must have elapsed since the
completion of myelosuppressive chemotherapy (4 weeks if prior nitrosourea) and
resolution of all nonhematologic toxicities to ≤grade 1.

2. Biologic (anti-neoplastic agent):

- Oral tyrosine kinase inhibitors or other similar agents. At least 7 days
must have elapsed since the completion of therapy with a biologic agent and
all non-hematologic toxicities must have resolved to ≤grade 1 prior to
enrollment

- Anti-IGFR-1R and other monoclonal antibodies: the shorter of 3 half-lives or
6 weeks must have elapsed since previous monoclonal antibody therapy and
resolution of all non-hematologic toxicities to ≤grade 1 prior to enrollment

3. Myeloid Growth Factor: Must not have received within 1 week prior to entry into
this study (2 weeks in the case of PEG-filgrastim)

4. Radiotherapy: At least 4 weeks must have elapsed and all non-hematologic
toxicities must have resolved to ≤grade 1 prior to enrollment. Previously
radiated lesions cannot be used to assess response unless those sites are the
sites of disease progression

5. Stem cell transplant (SCT): For autologous SCT, ≥3 months must have elapsed. For
allogeneic SCT, ≥6 months must have elapsed and there must be no evidence of
active graft versus host disease

17. All acute toxicities related to prior treatment recovered to grade ≤1 , except
alopecia and hematologic parameters specified in the inclusion criteria

18. Willingness and ability to comply with the visit schedule and assessments required by
the study protocol, including effective birth control (Section 5.4) for sexually
active patients

Exclusion Criteria:

1. Investigator-predicted life expectancy of less than two months

2. Investigator-predicted inability to tolerate pixantrone monotherapy treatment adverse
effects for less than two months

3. Prior anthracycline treatment with a cumulative dose exceeding 450 mg/m2 (calculated
based on doxorubicin equivalents)

4. Active National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) ≥grade 3 infection, or a lower grade infection deemed resistant or refractory
to available antimicrobial agents, or infection requiring ongoing antibiotic treatment

5. Major surgery ≤7 days and/or with incomplete/inadequate wound healing prior to start
of study treatment

6. Known acute or chronic hepatitis B or hepatitis C virus infection

7. Known seropositivity for human immunodeficiency virus (HIV)

8. Any experimental/investigational therapy ≤28 days prior to start of study treatment

9. Myocardial infarction within the past 6 months

10. New York Heart Association class II, III or IV heart failure

11. Any contraindication, known allergy, or hypersensitivity to any investigational
drug(s)

12. Pregnant or lactating

13. Planned radiotherapy or surgical procedures for the qualifying malignancy

14. Any psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study procedures or follow-up schedules

15. Other severe and/or uncontrolled medical disease that could compromise participation
in the study, or any medical or psychiatric condition that, in the opinion of the
investigator, would make study drug administration hazardous or obscure the
interpretation of data