This study has been transitioned to CTIS with ID 2023-508050-26-00 check the CTIS register for the current data. Primary objective:•To establish the recommended phase 2 dose of Vyxeos®/CPX-351 in combination with clofarabine in children with…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Frequency of Dose-limiting toxicities (DLTs) during the first course of
therapy.
Secondary outcome
1. Safety and tolerability: frequency of AEs, frequency of laboratory
abnormalities and number of toxic deaths
2. Measures of anti-leukemic activity: ORR after 1 course and as best response
and ORR after 2 courses, which includes CR, CRi, and PR, determined by
morphology with flow cytometric confirmation.
3. Overall patient survival (OS) and relapse-free survival
4. Number of patients undergoing HSCT after treatment
Exploratory endpoints:
5. Serum and intracellular (as Ara-CTP accumulation in leukemic blasts)
pharmacokinetic parameters
6. Relationship between response (ORR) and Ara-CTP accumulation
7. Correlation between duration of response and measurable residual disease
(MRD) assessed by Flow-cytometry
Background summary
Treatment with intensive chemotherapy in AML results in approximately 70%
survival in newly diagnosed patients. Prognosis at relapse is worse and is in
the 30-40% range. Relapse treatment generally consists of one course of
fludarabine, cytarabine and liposomal daunorubicin (FLAG-DNX), followed by a
fludarabine and cytarabine course and subsequent stem-cell transplantation.
Cytarabine has been used in combination with fludarabine and cladribine, with
the aim to induce synergism by increasing Ara-CTP (active cytotoxic metabolite
from ara-C) accumulation, which can be seen as a surrogate marker for
cytarabine induced cell-kill. Synergy with cytarabine can also be achieved with
clofarabine, which is a potent inhibitor of ribonucleotide reductase, leading
to a depletion of normal deoxynucleotides and subsequently to increased Ara-CTP
levels.
The phase IB trial ITCC020/I-BFM 2009-02 recently reported that clofarabine,
replacing fludarabine in the standardly used fludarabine, cytarabine and
liposomal daunorubicin (FLAG-DNX) combination regimen, showed high response
rates (Overall Response Rate - ORR 68% and 80% at the recommended phase 2 dose
- RP2D) in patients with refractory/relapsed AML, and was generally tolerable,
with infectious complications as the main side-effect due to the
immunosuppressive properties of clofarabine.
Currently DNX is unavailable, which urges the need to develop other treatment
blocks. The liposomal formulation of Vyxeos®/CPX-351 may be a suitable
replacement for DNX, considering the long-term side effect of cardiotoxicity
due to anthracyclines which is of primary importance in younger heavily
pre-treated patients. Preliminary results in pediatric and young adult patients
with relapsed/refractory AML in a COG study using Vyxeos®/(CPX-351) at a RP2D
of 135 U/m2 (AAML1421) showed encouraging ORR (80%), with 70% of patients
reaching CR/CRi as best response after single agent-treatment with Vyxeos®/
CPX-351. Preclinical data have also assessed an increased Ara-CTP accumulation
and cytotoxicity in immortalized cell lines, and confirmed by tests in ex-vivo
blasts from a cohort of AML patients (n=5), when cells were exposed to CPX-351
after 4 hours of incubation with fludarabine.
In this study we therefore evaluate Vyxeos®/CPX-351 in combination with
clofarabine in a phase 1b study with the aim to establish the RP2D of this
combination.
Study objective
This study has been transitioned to CTIS with ID 2023-508050-26-00 check the CTIS register for the current data.
Primary objective:
•To establish the recommended phase 2 dose of Vyxeos®/CPX-351 in combination
with clofarabine in children with relapsed/refractory AML
Secondary objectives:
•To determine the safety and tolerability of this combination
•To determine the (preliminary) efficacy in terms of the hematological
remission rate in these patients as determined by morphology with flow
cytometric confirmation.
•To describe the durability of response, including the number of patients that
undergo stem- cell transplant after re-induction with this regimen
Exploratory objectives:
• To describe the serum and intracellular pharmacokinetics parameters of
CPX-351 in combination with clofarabine.
• To describe the relationship between response (ORR) and intracellular Ara-CTP
accumulation
• To describe the correlation between duration of response and measurable
residual disease assessed by Flow-cytometry
Study design
This is an open label, non-randomized, Phase 1b dose-finding study following a
Rolling-6 design, with a dose escalation part followed by an expansion cohort
to better characterize safety at the RP2D. CPX-351 is the investigational
medicinal product in this study and will be made available by Jazz
Pharmaceuticals for this study. Clofarabine should be used from commercial
stock according to the Summary of Product Characteristics (SPC).
Intervention
Treatment will consist of 2 courses. A combination of Vyxeos®/CPX-351 given at
day 1, 3, 5 with clofarabine given at day 2-6 will be administered in course 1,
and Vyxeos®/CPX-351 only in course 2.
The infusion schedule for Course 1 is as follows:
• Vyxeos®/CPX-351 ® will be infused over 90 minutes on day 1, 3 and 5 only, 3
hours after the end of clofarabine administration if given on the same day.
• Clofarabine infusion will be given over 2 hours IV, daily on day 2-6.
In Course 2, Vyxeos®/CPX-351 will be administered as single-agent, at the same
DL and with the same infusion schedule of Course 1.
Study burden and risks
The invasive procedures related to the study are the same expected as per
standard of care. Patients will undergo some additional tests required per
protocol, i.e. pregnancy tests, if applicable, PK samples collection (which are
performed through the available central line already in place for all patients).
Risks associated with this study are mainly the anticipated side-effects of
Vyxeos®/CPX-351 in combination with Clofarabine. The major toxicities expected
by both compounds are related to prolonged myelosuppression and subsequent
possible (fungal) infections.
In the ITCC020/I-BFM 2009-02 study with Clofarabine, 3 pulmonary aspergillosis
occurred in 34 patients included; therefore to mitigate the risk in the current
study we planned to screen patients with CT thorax and galactomannan antigen
before the enrollment. In the COG Vyxeos®/CPX-351 study, toxicity was
consistent with historical intensive AML regimens, but the number of pediatric
patients treated with this compound is still limited. In addition Vyxeos®/
CPX-351 has not been combined before with clofarabine.
To mitigate the overlapping hematologic toxicity, we will test only the
approved dose of Vyxeos®/CPX-351 for adults (at 44 mg/m2 of Daunorubicin and
100 mg/m2 of Cytarabin/dose) with increasing dosages of Clofarabine, starting
from DL1 with a 50% lower dose of clofarabine compared to the RP2D established
in the ITCC020/I-BFM 2009-02.
Prognosis for relapsed/refractory AML is dismal and in the 30-40% range and
historical regimens for these patients are intensive. Considering to
potentially improve the outcome with this new regimen and expecting comparable
toxicity with other available treatments, we think that the potential benefits
of the study outweigh the potential toxicity in these patients. Regarding
long-term cardiotoxicity, the study regimen can provide additional benefit
compared to other available regimens, since liposomal daunorubicin (DNX) is
currently unavailable. The liposomal formulation of Vyxeos®/CPX-351 can
replace the benefit of DNX in terms of long-term cardiac toxicity, which is of
primary importance in younger pre-treated patients. However, there are no data
as yet on long-term cardiac follow-up after using DNX instead non-liposomal
formulation of anthracyclines. In the COG Phase I study of Vyxeos®/CPX-351, 1
grade 3 cardiotoxicity was registered.
Toxicity will be closely monitored and if necessary the study will be stopped
due to significant safety concerns in accordance with the early stopping rules.
Sites will be prompted to collect data on toxicity.
Heidelberglaan 25
Utrecht 3584 CS
NL
Heidelberglaan 25
Utrecht 3584 CS
NL
Listed location countries
Age
Inclusion criteria
• Age >=1 year and <=21 years
• Any >= 2nd relapse of AML
• Refractory AML (defined as >= 20% blasts in the bone marrow after standard
(re-) induction therapy)
• Early 1st relapse (defined as relapse within one year from initial diagnosis)
of AML
• Any relapse of AML after prior allogeneic HSCT
• Any relapse of AML with high risk cytogenetic characteristics (as defined in
Appendix V)
• Complete initial work-up within 7 days prior to study entry, including
bone-marrow aspiration, lumbar puncture (without intrathecal therapy)
• Lansky play score >= 60 for patients <16 years of age; or Karnofsky
performance status >= 60 for patients >= 16 years of age (see Appendix I for
Performance scales).
• Life expectancy > 6 weeks
• The patient must have a calculated GFR >= 70mL/min/1.73 m2.
• Liver function: total serum bilirubin <= 3 mg/dl or 50 µmol/L and aspartate
transaminase (AST) and alanine transaminase (ALT) <=200 U/L
• Adequate cardiac function (defined as shortening fraction >=28% or ejection
fraction >=50%)
• For female patients with childbearing potential, a negative test for
pregnancy is to be performed before entry on study.
• Male and female patients must use a highly effective contraceptive method
during the study and for a minimum of 6 months after study treatment.
• Female patients may not breastfeed during the study and for a minimum of 3
months after study treatment.
• Absence of any psychological, familial, sociological or geographical
condition potentially hampering compliance with the study protocol and
follow-up schedule is required; those conditions should be discussed with the
patient before registration in the trial.
• Before patient registration, written informed consent must be given according
to ICH/GCP, and national/local regulations.
Concomitant treatments:
• Concomitant administration of any other experimental drug under
investigation, or concurrent treatment with any other anti-cancer therapy other
than specified in the protocol is not allowed.
• GCSF will not be used for priming and no routine GCSF support is allowed
during the 1st course, except for life-threatening infections.
Additional criteria:
• At least 6 patients must be enrolled with an M3 or a WBC count >10x109/L
with blasts
Exclusion criteria
• Evidence of a currently uncontrolled bacterial, viral or parasitic infection
• Evidence of a fungal infection, defined as either:
- Pulmonary infiltrates suggestive of a fungal infection at HR-CT (within 3
weeks prior to enrollment) - Positive Aspergillus serum test (galactomannan),
according to local laboratory practice (within 3 weeks prior to enrollment)
• Evidence of isolated extramedullary relapse, including isolated CNS-relapse
• Evidence of CNS3 or symptomatic CNS leukemia
• Down Syndrome
• Evidence of relapsed/refractory acute promyelocytic leukemia (APL)
• Use of any anticancer therapy within 2 weeks before study entry. The patient
must have recovered from all acute toxicities from any previous therapy (note:
hematological toxicities do not need to be considered since the patient has
overt leukemia)
• History of prior veno-occlusive disease (VOD)
• Known hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin
• Copper metabolism deficiency, such as Wilson's disease
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508050-26-00 |
| EudraCT | EUCTR2020-000142-34-NL |
| CCMO | NL72866.041.20 |
| Other | NL8134 |