Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations

  • STATUS
    Recruiting
  • days left to enroll
    32
  • participants needed
    1600
  • sponsor
    Cardiff University
Updated on 23 January 2021
remission
myeloid leukemia
cytarabine
flow cytometry
decitabine
leukemia
daunorubicin
residual tumor
ara-c
azacitidine
secondary acute myeloid leukemia
gemtuzumab
cytarabine/daunorubicin
blast cells
cladribine
mylotarg
vosaroxin
gemtuzumab ozogamicin
myelodysplastic syndrome with excess blasts-2
high risk myelodysplastic syndrome

Summary

The AML18 Trial will evaluate several relevant therapeutic questions in Acute Myeloid Leukaemia (AML), as defined by the WHO, and High Risk Myelodysplastic Syndrome. The trial is primarily designed for patients over 60 years considered fit for an intensive chemotherapeutic approach, but younger patients who may not be considered suitable for the concurrent NCRI AML Trial for younger patients may also enter. Patients for whom intensive chemotherapy is not thought suitable may enter the concurrent NCRI trial of less intensive therapy (LI1). Approximately 1600 patients will be recruited.

At entry, a randomisation will compare a standard chemotherapy schedule DA (Daunorubicin/Ara-C) combined with 1 dose of Mylotarg (gemtuzumab ozogamicin, or GO) in course 1 against CPX-351. Patients who have known adverse risk cytogenetics (using Grimwade 2010 classification favourable/intermediate/adverse) at diagnosis may enter a Phase 2 evaluation of the combination of Vosaroxin plus Decitabine. Patients who achieve complete remission (CR) and who are MRD negative by flow cytometry after course one of DA will receive one further course of DA, with a randomisation to receive, either a course of DA or intermediate dose Cytarabine (IDAC) as a third course. Patients who are MRD negative by flow cytometry after course one of CPX-351 will receive up to 2 further course of CPX. Patients who fail to achieve a CR after course 1 of DA or who are MRD positive by flow cytometry or for whom MRD information is not available, are eligible to be randomised to compare DA with DA plus Cladribine (DAC) or FLAG-Ida for up to two courses of therapy. Patients who fail to achieve a CR after course 1 of CPX-351 or who are MRD positive by flow cytometry or for whom MRD information is not available are eligible to be randomised between a second course of standard dose CPX versus a repeat of the course 1 schedule. Patients receiving Vosaroxin and Decitabine are excluded from these post course 1 randomisations .

Following the outcome of course 1, patients who received DA chemotherapy on course 1 will be randomised to receive further chemotherapy with the 2nd generation FLT3 inhibitor AC220. Patients randomised to AC220 will be allocated a maximum of 3 courses (short AC220) or 3 courses plus maintenance for 1 year (long AC220). Patients receiving Vosaroxin and Decitabine are excluded from this randomisation.

Patients will be eligible for a non-intensive allogeneic stem cell transplant if a suitable HLA matched donor is available.

Description

AML18 is a trial primarily for older patients with AML and high risk Myelodysplastic Syndrome (MDS). It offers a randomised controlled Phase II/III trial which uses a factorial design for maximum efficiency to evaluate two induction options followed by treatment with small molecule beyond course 1, and dose intensification for patients without evidence of MRD negativity.

There are five randomised comparisons within the trial:

  1. At diagnosis:

For patients not known to have adverse risk cytogenetics DA chemotherapy plus a single dose of 3 mg/m2 of Mylotarg versus CPX-351. Patients with abnormal LFTs can enter the randomisation but receive DA alone or CPX-351.

2. For patients who received DA chemotherapy but are not in CR or who are MRD +ve, or for whom MRD is not assessable.

DA versus DAC versus FLAG-Ida

3. All patients at second course who have received DA and have not received Vosaroxin and Decitabine induction AC220 versus no AC220 for a maximum of 3 cycles; then with or without maintenance for 1 year for patients allocated AC220

4. For patients who are in CR or CRi and MRD -ve post course1 and have completed 2 courses of DA DA versus intermediate dose Cytarabine (IDAC)

5. For patients who received CPX-351 chemotherapy but are not in CR or who are MRD +ve, or for whom MRD is not assessable CPX-351 100 units/m2 x 3 doses versus CPX-351 100 units/m2 x 2 doses

The trial will also assess:

  • Non-intensive allogeneic stem cell transplant for patients with matched sibling or matched unrelated donors.
  • The combination of Vosaroxin and Decitabine for those with known adverse risk cytogenetics at diagnosis

Details
Condition Bone marrow disorder, Bone marrow disorder, Preleukemia, Acute myeloid leukemia, Acute Myelogenous Leukemia (AML), Acute myeloid leukemia, MYELODYSPLASTIC SYNDROME, Myelodysplastic Syndromes (MDS), Myelodysplastic Syndromes (MDS), Acute Myelogenous Leukemia (AML), myelodysplastic syndromes, myelodysplastic syndrome (mds), acute myelogenous leukemia, anll, acute myeloblastic leukemia
Treatment Ganetespib, Arm A Mylotarg, Arm D Cladribine, AC220, Arm A Mylotarg plus DA Versus CPX-351, Arm B Vosaroxin and Decitabine, Arm D Small molecule or Not, Arm C DA V FLAG-Ida V DAC, Arm E CPX-351 (200 V 300), Arm F DA V IDAC
Clinical Study IdentifierNCT02272478
SponsorCardiff University
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients are eligible for the AML18 trial if
They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de novo or secondary AML - or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB-2). (NB patients with prior MDS (>10% blasts, RAEB2) have received azacitidine are not eligible for the trial, but patients with <10% who have failed a hypomethylating agent and developed AML may enter the trial)
Patients should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the MRC AML19 trial please contact the trial team for further information
Patients entering the Vosaroxin/Decitabine arm must be over the age of 60 and have known adverse risk cytogenetics
They have given written informed consent
Serum creatinine 1.5 ULN (upper limit of normal)
Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Men should be advised to not father a child while receiving trial treatment. Similarly women must agree to adequate contraceptive measures and avoid becoming pregnant while on protocol treatment. In both males and females these measures must be in place for at least 3 months following completion of Decitabine and at least 6 months after the last administration of Cladribine. The time period following treatment with Decitabine where it is safe to become pregnant is unknown. In the event of pregnancy at any point during the trial, the IMPs should be immediately stopped and the Trial Team should be contacted and pregnancy reporting procedures followed
ECOG Performance Status of 0-2

Exclusion Criteria

Patients are not eligible for the AML18 trial if
They have previously received cytotoxic chemotherapy for AML [Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy, is not an exclusion]
They are in blast transformation of chronic myeloid leukaemia (CML)
They have a concurrent active malignancy excluding basal cell carcinoma
They are pregnant or lactating
They have Acute Promyelocytic Leukaemia
Known infection with human immunodeficiency virus (HIV)
Patients with prior cumulative anthracycline exposure (from prior treatment of a non AML cancer) of greater than 300 mg/m2 daunorubicin (or equivalent)
History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry
Specific exclusion criteria for the Mylotarg Arm
Pre-existing liver impairment with known cirrhosis
Total bilirubin > 1.5 x the upper limit of normal (ULN)
Aspartate aminotransferase (AST) > 2.5 x ULN
Alanine aminotransferase (ALT) > 2.5 x ULN
Specific exclusion criteria for the Vosaroxin/Decitabine Entry
Total bilirubin > 1.5 x the upper limit of normal (ULN)
Aspartate aminotransferase (AST) > 2.5 x ULN
Alanine aminotransferase (ALT) > 2.5 x ULN
Left ventricular ejection fraction (LVEF) < 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)]
Specific exclusion criteria for CPX-351 treatment
Hypersensitivity to cytarabine, daunorubicin or liposomal products
History of Wilson's disease or other copper-metabolism disorder
Specific exclusion criteria for Cladribine
Patient's serum creatinine must be within the local ULN to enter the
randomisation. Patients for whom this is not the case can be randomised
between the remaining options
In addition patients are not eligible for the AC220 randomisation if they
have
Cardiovascular System Exclusion Criteria
Known serious cardiac illness or medical conditions, including but not limited
to
I. Clinically unstable cardiac disease, including unstable atrial
fibrillation, symptomatic bradycardia, unstable congestive heart failure
active myocardial ischemia, or indwelling temporary pacemaker II. Ventricular
tachycardia or a supraventricular tachycardia that requires treatment with a
Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or
Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of
other antiarrhythmic drugs is permitted
III. Use of medications that have been linked to the occurrence of torsades de
pointes (see Appendix for the list of such medications) IV. Second- or third-
degree atrioventricular (AV) block unless treated with a permanent pacemaker
V. Complete left bundle branch block (LBBB) VI. History of long QT Syndrome or
a family member with this condition VII. Serum potassium, magnesium, and
calcium levels not outside the laboratory's reference range VIII. QTc >450 ms
(average of triplicate ECG recordings); a consistent method of QTc calculation
must be used for each patient's QTc measurements. QTcF (Fridericia's formula)
is preferred. Please see the trial website for QTcF calculator
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note