1.

2 Trial schema:
UKALL14 TRIAL SCHEMA
Phase 1 Induction (4 weeks): precursor B cell & T cell patients (Philadelphia –ve patients only) to receive Pegylated-Asparaginase plus standard phase 1 induction therapy

Pre B-cell ALL

T-cell ALL

B1: Standard Phase 1 Therapy B2: Standard Phase 1 Therapy

Standard Phase 1 Therapy
Alone + CD20 (Rituximab)

Phase 2 Induction (4 weeks): precursor B cell & T cell patients to receive standard phase 2 induction therapy

Pre B-cell ALL T-cell ALL

T2: Standard Phase 2 Therapy

Standard Phase 2 Therapy T1: Standard Phase 2 Therapy + Nelarabine

PATIENTS IN COMPLETE REMISSION (CR) – Risk Assessment performed on all patients at this time point

SIBLING DONOR NO SIBLING DONOR

High Risk Standard Risk

*
Over 40 years old * *
40 years and under Over 40 years old *
Intensification with HD- 40 years and under
Myeloablative: Conditioning with Continue methotrexate
Intensification with HD-Methotrexate +
Methotrexate + PEG-ASP Myeloablative: Conditioning with
Etopside-TBI or Cyclophosphamide TBITo intensification,
PEG-ASP Etopside-TBI or Cyclophosphamide TBI
receive allo SCT (sibling) consolidation and
Conditioning regimen with maintenance
Conditioning regimen with fludarabine- To receive allo SCT (MUD)
fludarabine-melphalan and
melphalan and Alemtuzumab
Alemtuzumab

To receive allo SCT (MUD)

To receive allo SCT (sibling)
*
P1: Standard P2: Collapsed Randomisation to Age at study entry
P1: Standard P2: Collapsed
Palifermin Dose
UKALL14 - Protocol - v5.0 20.07.12 Page 13 of 134
 Table 7.2.3a – Phase I induction

Route of
Drug Dose

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20

Day 21

Day 22

Day 23

Day 24

Day 25

Day 26

Day 27

Day 28
administration

Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Daunorubicin 30 mg/m2 IV 1 8 15 22
Vincristine*** 1.4mg/m2 IV
1 8 15 22
Max 2mg
Dexamethasone** 10mg/m2 PO 1 2 3 4 8 9 10 11 15 16 17 18
2
PEG- asparaginase 1000IU/m iv
Philadelphia
Positive patients 4* 18
should NOT be
given Pegylated
Asparaginase
Methotrexate# 12.5mg Intrathecal 14
Imatinib - Patients with Philadelphia positive disease
should also receive continuous daily Imatinib, PO,
starting at 400mg, aiming to escalate to 600mg within 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
weeks, if tolerated. This should be continued until
transplant wherever possible

*Om it Day 4 P egylated Asparaginase for P hiladelphia N egative patients OVER 40. These patients should only receive Day 18 Pegylated
Asparaginase.
**Dexamethasone should be capped at 20mg for larger patients
***Do not give azoles as antifungal prophylaxis within 72 hours before or after vincristine.
Notes on lumbar puncture and treatment of established CNS disease:
# Timing of Intrathecal therapy can be moved +/- 3 days to allow administration on specified lists as per local and national guidance.
In the case of traumatic lumbar puncture (> 10 red blood cells per microlitre), patients should be treated as having CNS disease IF they still have blasts
within the peripheral blood at the time of occurrence or have blasts in the CSF. In this case and in the case where there is existing evidence of established

UKALL14 - Protocol - v5.0 20.07.12 Page 39 of 134

 7.2.5 Phase 2 induction
Phase 2 induction, weeks 5-8 (please see section 7.2.4 for recovery pre-phase 2)
To be given to all patients regardless of phenotype. Patients with T-lineage ALL will be randomised to receive either Nelarabine as an additional course,
following phase 2 or no additional treatment.
Patients with Philadelphia positive ALL should also receive continuous daily Imatinib, PO, starting at 400mg, aiming to escalate to 600mg within 2 weeks, if
tolerated.

Table 7.2.5a – Phase 2 Induction

Route of

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20

Day 21

Day 22

Day 23

Day 24

Day 25

Day 26

Day 27

Day 28
Drug Dose

1
2
3
4
5
6
7
8
9
administration

Day
Day
Day
Day
Day
Day
Day
Day
Day
Cyclophosphamide* 1000 IV
1 15
mg/m2
Cytarabine# 75mg/ IV
2 3 4 5 9 10 11 12 16 17 18 19 23 24 25 26
m2
Mercaptopurine 60mg/ PO
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
m2
Methotrexate# 12.5mg Intrathecal 1 8 15 22

Imatinib - Patients with Philadelphia positive disease

should also receive continuous daily Imatinib, PO, starting at
400mg, aiming to escalate to 600mg within 2 weeks, if 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
tolerated. This should be continued until transplant
wherever possible
# Timing of Intrathecal therapy can be moved +/- 3 days to allow administration on specified lists as per local and national guidance. Likewise, timing of the
cytarabine blocks can be scheduled so that they can take place during the week as long as the full doses are given.
* Cyclophosphamide 1000mg/m2 IV over 20-30 minutes on days 1 and 15. Give 125 mls/m2/hour of Dextrose/ Saline for 30 minutes before cyclophosphamide
and for 3.5 hours afterwards ie 4 hours in total. Do not add potassium. Mesna is not needed.'

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 Table 7.2.7 – Intensification/CNS prophylaxis

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20

Day 21

Day 22

Day 23

Day 24

Day 25

Day 26

Day 27

Day 28
1
2
3
4
5
6
7
8
9
Route of
Drug Dose

Day
Day
Day
Day
Day
Day
Day
Day
Day
administration

Methotrexate* 3 g/m2 IV 1 15
PEG- asparaginase** 1000IU/ IV
2 16
m2
Imatinib - Patients with Philadelphia positive disease
should also receive continuous daily Imatinib, PO, starting at
400mg, aiming to escalate to 600mg within 2 weeks, if 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
tolerated. This should be continued until transplant wherever
possible
*Please consult appendix 15 for full guidance on administration of High Dose MTX – (please note: after treatment with methotrexate, folinic acid rescue must
be given. Please see Appendix 15 for details).
**Please note as detailed in section 8.2.1 and Appendix 7:
Specimens for local Specimens for correlative studies to be
assessment sent to central laboratory (see app 8)*
During 5ml peripheral blood in a serum tube (for
intensification: Asparaginase activity assay and anti-
Asparaginase antibodies) taken on d2 and
d16 of intensification (immediately prior to
doses 3 and 4 of peg-asp)

On the same day (d3 or d4), a 4.5 ml sodium

citrate tube should be filled (to the line) to
collect plasma. Spin the tube @ 2000G for 5
mins, aliquot serum into 5 eppendorfs and
store locally at –80°C if possible or if not, -
20°C.

UKALL14 - Protocol - v5.0 20.07.12 Page 46 of 134

7.2.8 Consolidation therapy
To be given to patients not eligible for transplantation. The first cycle of consolidation therapy should begin after intensification, when neutrophils > 0.75 x
109/L and platelet > 75 x 109/L (Please see tables 7.2.8 a-d for details). For patients with central nervous system involvement, cranial irradition will be given
before consolidation begins. Maintenance therapy with 6-Mercaptopurine should be given throughout the period of CNS irradiation. In the event of cytopenias,
6-Mercaptopurine therapy should be reduced or omitted rather than radiotherapy being delayed. The dose of thiopurine should not be increased as per the
maintenance protocol but should be continued at 75mg/m2 in the absence of cytopenias.

Table 7.2.8a - Cycle 1 Consolidation – to begin after intensification , when neutrophils > 0.75 x 109/L and platelet > 75 x 109/L.

Drug Dose Route of Day Day Day Day Day Day Day
administration 1 2 3 4 5 6 7
Cytarabine 75mg/m2 IV 1 2 3 4 5
2
Etoposide 100mg/m IV 1 2 3 4 5
PEG- asparaginase 1000 IU/m2 IV 5
Methotrexate# 12.5 mg Intrathecal 1
Imatinib - Patients with Philadelphia positive disease should also
receive continuous daily Imatinib, PO, starting at 400mg, aiming to
1 2 3 4 5 6 7
escalate to 600mg within 2 weeks, if tolerated. . This should be
continued until transplant wherever possible

# Timing of Intrathecal therapy can be moved +/- 3 days to allow administration on specified lists as per local and national guidance. Likewise, timing of the
cytarabine blocks can be scheduled so that they can take place during the week as long as the full doses are given.

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Table 7.2.8b - Cycle 2 Consolidation – to commence 3 weeks from day one cycle 1 or when neturophils are >0.75 x 109/l
and platelets >75 x 109/l

Drug Dose Route of administration

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7
Cytarabine 75mg/m2 IV 1 2 3 4 5
Etoposide 100mg/m2 IV 1 2 3 4 5
Methotrexate 12.5 mg Intrathecal 1
Imatinib - Patients with Philadelphia positive disease should also receive continuous daily Imatinib, PO, starting at
400mg, aiming to escalate to 600mg within 2 weeks, if tolerated. . This should be continued until transplant wherever 1 2 3 4 5 6 7
possible

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 Table 7.2.8ci – Cycle 3 (DAYS 1-28) - Consolidation/Delayed intensification - to commence 3 weeks from day one cycle 2 or when
neutrophil count> 0.75 x 109/L and platelets >75 x 109/l
DAYS 1-28

Route of
Drug Dose

Day 10

Day 11

Day 12

Day 13

Day 14

Day 15

Day 16

Day 17

Day 18

Day 19

Day 20

Day 21

Day 22

Day 23

Day 24

Day 25

Day 26

Day 27

Day 28
administration

Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Daunorubicin 25mg/m2 IV 1 8 15 22
2
Vincristine 1.4mg/m IV
1 8 15 22
(Max 2mg)
Peg-asparaginase 1,000 IU/m2 IV 4

Dexamethasone* 10mg/m2 PO 1 2 3 4 8 9 10 11 15 16 17 18 22 23 24 25

Methotrexate 12.5 mg Intrathecal 2 17

Imatinib - Patients with Philadelphia positive disease

should also receive continuous daily Imatinib, PO,
starting at 400mg, aiming to escalate to 600mg within 2 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
weeks, if tolerated. . This should be continued until
transplant wherever possible

*Dexamethasone should be capped at 20mg for larger patients.

This phase runs from day 1 to day 42 inclusive (i.e. 6 weeks). Patients should have ANC >0.75x109/L and platelets of >75x109/L to start and have recovered
again to this level from before the 29th day of therapy is started. Once begun, therapy is not interrupted for myelosuppression alone. Any serious infection,
such as Varicella, pneumocystis pneumonia, or neutropenia with fever, and presumed or proven infection, warrants chemotherapy interruption at any time
during this block. Before the patient completes day 29-42 (table 7.2.8cii), i.e. before the d29 cyclophosphamide, the counts should be ANC >0.75x109/L and
platelets of >75x109/L

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Table 7.2.8cii – Cycle 3 (DAYS 29-42) – Consolidation/Delayed intensification - to commence 3 weeks and 29 days from day one cycle 2 or
when neutrophil count> 0.75 x 109/L and platelets >75 x 109/l

DAYS 29-42

Route of

Day 29*
Drug Dose

Day 30

Day 31

Day 32

Day 33

Day 34

Day 35

Day 36

Day 37

Day 38

Day 39

Day 40

Day 41

Day 42
administration

Cyclophosphamide 1000 mg/m2 IV 29

2
Cytarabine 75mg/m IV 30 31 32 33 37 38 39 40
Mercaptopurine 60mg/m2 PO 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Imatinib - Patients with Philadelphia positive disease should also
receive continuous daily Imatinib, PO, starting at 400mg, aiming to escalate
to 600mg within 2 weeks, if tolerated. . This should be continued until 29 30 31 32 33 34 35 36 37 38 39 40 41 42
transplant wherever possible

This phase runs from day 1 to day 42 inclusive (i.e. 6 weeks). Patients should have ANC >0.75x109/L and platelets of >75x109/L to start and have recovered
again to this level from before the 29th day of therapy is started. Once begun, therapy is not interrupted for myelosuppression alone. Any serious infection,
such as Varicella, pneumocystis pneumonia, or neutropenia with fever, and presumed or proven infection, warrants chemotherapy interruption at any time
during this block. Before the patient completes day 29-42 (table 7.2.8cii), i.e. before the d29 cyclophosphamide, the counts should be ANC >0.75x109/L and
platelets of >75x109/L.

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Table 7.2.8d - Cycle 4 – Consolidation: Identical to Cycle 2, and will begin when neutrophils > 0.75 x 109/L and platelets >75 x 109/l

Route of

Day -1
Drug Dose

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7
administration

Cytarabine 75mg/m2 IV 1 2 3 4 5
Etoposide 100mg/m2 IV 1 2 3 4 5
Methotrexate 12.5mg Intrathecal 1
Imatinib - Patients with Philadelphia positive disease
should also receive continuous daily Imatinib, PO, starting
at 400mg, aiming to escalate to 600mg within 2 weeks, if 1 2 3 4 5 6 7
tolerated. . This should be continued until transplant
wherever possible

UKALL14 - Protocol - v5.0 20.07.12 Page 51 of 134

7.2.9 Maintenance therapy (non-transplant patients only)
To start as soon as neutrophils are 0.75 x 109/l and platelets are 75 x 109/l following consolidation 4 and to
continue for 2 full years.
Patients with Philidelphia positive disease should continue with daily Imatinib throughout maintenance.
Table 7.2.9 – Maintenance therapy
Drug Dose Route of administration Frequency
Vincristine 1.4 mg/m2 IV every 3 months
(max 2 mg/dose)
Prednisolone 60 mg/m2 PO 5 days every 3 months
Mercaptopurine* 75 mg/m2 PO Daily
2
Methotrexate* 20 mg/m PO or IV once per week (not to
be given on the same
day at the Co-
trimoxazole)
Intrathecal therapy during maintenance (to be given once neutrophils reach 0.75 x 109/l and platelets
reach 75 x 109/l)
Methotrexate 12.5mg Intrathecal Every 3 months

Dosing of maintenance therapy should be adjusted to maintain the neutrophil count between 0.75 and 1.5 x
109/l and platelet count between 75 and 150 x 109/l.
*Dose of MP and MTX should be alterered in 25% increments or decrements to achieve the above
counts. eg if neutrophils > 1.5 x 109/l, increase 6-MP dose by 25%. If neutrophils remain > 1.5 x 109/l after
4 weeks, increase MTX by 25% etc. There are no maximum doses of MP and MTX. If neutrophils fall below
0.75 x 109/l, reduce both drugs by 50%, if neutrophils fall below 0.5 x 109/l, stop maintenance and restart at
100% when neutrophils > 0.75 x 109/l. Similar adjustments need to be made for the platelet count to
maintain above counts.

Maintenance should not be interrupted unnecessarily but if doses are omitted for cytopaenias or infectious
complications, they do not need to be made up with additional doses later.
Co-trimoxazole (960mg bd, twice per week, not on the same day as the weekly oral MTX) and aciclovir
(200mg bd) prophylaxis against PCP and HSV/VZV reactivation should be given throughout maintenance.
Local practice may be followed regarding the aciclovir dose if necessary.
If cytopaenias occur and maintenance is halted, consideration should be given to stopping the co-
trimoxazole if blood counts do not recover within 2-3 weeks. Doses of mercaptopurine and MTX should not
be compromised in order to permit continuation of co-trimoxazole.
Alternative prophylaxis against PCP should be given, for example monthly nebulised pentamindine, or oral
dapsone.

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