AML, AdultPhase 2PALMNCT05025098
Precision Therapy Versus Standard Therapy in AML and MDS in Elderly
A Phase 2 study testing Standard therapy and Precision therapy in people with AML, Adult and MDS, run by University Hospital, Akershus at 1 site in Norway.
Trial summary
This is a randomized clinical trial that randomizes between treatment principles. The study will investigate if precision therapy determined by a tumour board is better than standard treatment for acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) in elderly. Read more about this study
- Who is it for?
- Ages 60 years and older
- Conditions the study is for
- AML, Adult, MDS
- What is being tested?
- Standard therapy and Precision therapy
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 1 siteNorway
- Study dates
- 22 Jun 2021to 10 Jun 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease and therapy-related AML (not if they have received antileukemic/mds treatment)), or
- acute leukemias of ambiguous lineage according to WHO 2016 or a diagnosis of myelodysplastic syndrome (MDS) with IPSS-R > 4.5.1
- Patients 60 years and older.
- Patients must NOT be eligible for intensive chemotherapy or allogeneic stem cell therapy (See Chapter 23.3)
- WBC ≤ 25 x109/L (prior hydroxyurea allowed for a maximum of 14 days, stopped before start of treatment)
- Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
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- WHO performance status 0, 1 or 2 for subjects ≥ 75 years of age OR 0 to 3 for subjects ≥ 60 to 74 years of age.
- Life-expectancy above 3 months
- Signed Informed Conscent
- Male Subjects Only: Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice contraception with condom. Male subjects must agree to refrain from sperm donation from initial study drug administration until at least 90 days after the last dose of study drug.
Who cannot join
- Acute promyelocytic leukemia.
- AML with favourable cytogenetic or genetic changes in patients who are fit for intensive chemotherapy. Favourable genetics are: t(8;21)(q22;q22.1); RUNX1-RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†; Biallelic mutated CEBPA
- Patients previously treated for AML or MDS (any antileukemic therapy or MDS treatment including investigational agents).
- Patients where it is not possible to get bone-marrow for NGS, i.e., "dry tap".
- Diagnosis of any previous or concomitant malignancy is an exclusion criterion: except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization.
- Blast crisis of chronic myeloid leukemia.
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- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)
- Cardiac dysfunction as defined by:
- Unstable angina or
- New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue,palpitations, dyspnea, or angina pain or
- Unstable cardiac arrhythmias
- Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance with the study protocol and follow-up schedule.
- Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
- Patients who do not understand the Written Informed Consent (e.g., language problems)
- Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea.
- Subject is known to be positive for HIV (HIV testing is not required).
- Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required).
- AML subjects that has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of venetoclax treatment.
- Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. Additional exclusion criteria at the time of randomization
- WHO performance status > 2 for subjects ≥ 75 years of age OR > 3 for subjects ≥ 60 to 74 years of age.
- Progressive disease according to ELN criteria (see chapter 12 Response evaluation)
- Initial treatment has made the patient eligible for allogeneic stemcell transplantation
- In addition, it will be specific exclusion criteria for the patients receiving targeted therapies related to the Summary of Product Characteristics (SPC) of each drug.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Norway1 site, 1 recruiting
- Recruiting
Akershus Universitetssykehus
Lørenskog
Anders Dahm, md.phd
About this study
Official title: Precision Therapy Versus Standard Therapy in Acute Myeloid Leukaemia and Myelodysplastic Syndrome in Elderly
This is a randomized clinical trial that randomizes between treatment principles. The study will investigate if precision therapy determined by a tumour board is better than standard treatment for acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) in elderly. The tumour board will decide the precision therapy based on identified genetic changes that can guide customized therapy. There are currently 40-50 targeted therapies approved for various cancers in Norway. The precision therapy will be given in addition to the standard treatment.
The primary study objective will be to evaluate the cost-effectiveness of a precision therapy strategy compared with standard treatment. Other objectives will mesaure efficacy and satety of the treatment, and impact on life quality of the patients.
Read the detailed description
Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in the elderly are not curable since elderly patients usually do not tolerate intensive chemotherapy and allogeneic stemcell transplantation. Next generation sequencing (NGS) of DNA can find changes in tumor DNA that can be targeted by new drugs, so called "precision therapy". Precision therapy drugs are usually less toxic than standard treatment, and thus may be particularly well suited for elderly. Precision therapy is principally different from today's standard therapy since it will be individualized based on NGS from the tumor, while in standard therapy all patients receive the same treatment. It is unknown how a precision therapy strategy will perform compared with standard therapy in AML and high-risk MDS in the elderly. A Clinical Tumour Board will decide on the precision therapy.
Study design:
This is a prospective, open label, single centre, randomized phase II clinical trial. The study randomizes between standard treatment and precision therapy in unfit elderly patients with AML and high-risk MDS. Importantly, this study design is not a randomization between treatments as in a traditional clinical trial, but a randomization between treatment principles. This means that patients in the standard treatment arm will receive the same treatment, while patients in the precision arm will receive different treatments based on the profiling of the tumor cells. Since most of the precision therapies will be experimental, the study is designed so that the patients in both arms receive a period of standard treatment before randomization. This is to reduce the risk of patients not receiving effective treatment, so that the precision therapy can be tested safely. The standard treatment for AML and high-risk MDS in elderly may change during the study, therefore "standard treatment" is defined as the recommended treatment in Norway at any time point. This means that MDS patients and AML patients may have different standard therapy.
Diagnostic sampling and genomic profiling will be done on the bone marrow of all included patients before start of treatment and compared with germline DNA from buccal swab taken at the bone-marrow. Treatment with hydroxyurea prior to the initial standard treatment is allowed to get leukocytes below 30.
While the patient receive two initial 28 day cycles of standard treatment, NGS of the bone marrow samples are done and assessed in the diagnostic pipeline, followed by bioinformatics analysis. The information is then interpreted by a Clinical Tumour Board consisting of pathologists, haematologists, oncologists, molecular biologists and bioinformatician, the treating hematologist and study nurse. The Clinical Tumour Board makes the decision on targeted treatment.
After initial standard therapy bone marrow samples will be evaluated for response to treatment. Patients with progressive disease as defined by the European Leukemia Net will go out of the study and receive treatment according to investigators choice. Notably, the results from the Clinical Tumour Board will be available for these patients to provide best possible treatment.
Patients without disease progression are randomized in a stratified manner 2:1 after the initial treatment with standard therapy to either precision therapy advised by the Clinical Tumour Board or continuous standard therapy.
- Conditions
- AML, Adult, MDS
- Being tested
- Standard therapy, Precision therapy
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Standard therapyDrug
Also called Azacitidine + venetoclax for AML patients. Azacitidine for MDS patients.
For AML patients: Venetoclax will be administered orally once daily Days 1 through 28, of a 28-day cycle, with a designated dose of 400 mg daily after ramp up in Cycle 1. During Cycle 1 Days 1 - 3, the dose of Venetoclax will ramp up from 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3. Azacitidine (100 mg/m2) is given once daily following administration of venetoclax for 5 days of every cycle, starting on Day 1 of each cycle.
For MDS patients: Azacitidine (100 mg/m2) is given once daily for 5 days of every 28 day cycle, starting on day 1 of each cycle.
Precision therapyDrug
Also called Standard therapy + tumor board decided precision therapy drug.
Precision therapy for both AML and MDS patients is standard therapy + tumor board determined precision therapy. The tumor board determined precision therapy can be all available drugs with a marketing authorization in Norway.
| Study group | Role | What they receive |
|---|---|---|
| Standard therapy | Active comparator | This study is a randomization between treatment principles, not treatments, i.e., standard therapy vs precision therapy (tumor board determined).
Standard treatment for AML patients is Azacitidine + Venetoclax.*
*Only if venetoclax is available to the study at the time-point of study start. If venetoclax is not available AML patients will receive Azacitidine alone similar to MDS patients.
Standard treatment for MDS is Azacitidine. Receives: Drug: Standard therapy |
| Precision therapy | Experimental | This study is a randomization between treatment principles, not treatments, i.e., standard therapy vs precision therapy (tumor board determined). The precision therapy arm will receive standard therapy + tumor board decided precision therapy. The tumor board decided precision therapy can in principle be any therapy with marketing authorization in Norway. Receives: Drug: Standard therapy; Drug: Precision therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
cost-effectiveness of a precision therapy
To evaluate the cost-effectiveness of a precision therapy strategy compared with standard treatment. The total cost of the treatment will be calculated and divided on health related quality of life (HRQoL)
Measured: 4-5 years
Secondary outcomes (16)
Event free survival
Median event free survival, i.e., the number of days to death or progression of the disease (whichever comes first)with AML or MDS
Measured: 4-5 years
Overall survival
Median overall survival
Measured: 4-5 years
Adverse events
The number of adverse events.
Measured: 4-5 years
Toxicity
The number of adverse events with CTCAE grade 3 or more
Measured: 4-5 years
Transfusion independence
The number of erythrocyte- or thrombocyte-transfusionsCR: Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L; platelet count >100 x 109/L
CR with incomplete recovery (CRi):
All CR criteria except for residual neutropenia (<1.0 x 109/L) or thrombocytopenia (<100 x 109/L) PR:All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%
Measured: 4-5 years
Budget impact
Budget impact of providing targeted treatment to all eligible patients.
Measured: 4-5 years
Overall response rate
For AML overall response rate is defined as Complete remission (CR), CR with incomplete recovery (CRi), Morphologic leukemia-free state, or Partial remission. For MDS overall response rate is defined as Complete remission, Marrow Complete Response, or Partial remission.
Measured: 4-5 years
Quality of life
Difference in quality of life using EQ-5D questionnaire between treatment arms
Measured: 4-5 years
Total costs
Total costs of precision therapy.
Measured: 4-5 years
Progression
Median number of days to progression of MDS to AML.
Measured: 4-5 years
Sequencing quality
The fraction of sequencing results with quality good enough to make a decision.
Measured: 4-5 years
Dry tap
The fraction of patients who were excluded because of dry-tap.
Measured: 4-5 years
Person staff time
Person-time used to sequence
Measured: 4-5 years
Person-time used to find possible precision therapy
Person time on tumour board and preparations
Measured: 4-5 years
Patients with actionable targets
The fraction of patients with actionable targets.
Measured: 4-5 years
MDS progression to AML
The median time to AML progression for patients with MDS
Measured: 4-5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Aug 2021
- Study start22 Jun 2021
- Primary completion10 Jun 2026 (estimated)
- Study completion10 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (33)Papers the sponsor has linked to this study.
- Other trials for AML, AdultStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- randomized open label clinical study phase II
- Masking
- None (open label)
- Enrolment
- 36 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Akershus
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Anders Erik Astrup Dahm, University Hospital, Akershus
- Investigators
- Anders Erik Astrup Dahm, MD, PHD, Principal investigator, Akershus universitetssykehus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05025098
- Sponsor's protocol ID
- PALM
- Acronym
- PALM
- Status last verified
- Aug 2021
- First submitted
- 27 May 2021
- Last updated
- 27 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Pfeilstocker M, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Levis A, Luebbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SM, Miyazaki Y, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016 Aug 18;128(7):902-10. doi: 10.1182/blood-2016-02-700054. Epub 2016 Jun 22.
PubMed 27335276Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Dohner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. doi: 10.1056/NEJMoa0901409.
PubMed 19776405Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011 Feb 10;29(5):487-94. doi: 10.1200/JCO.2010.30.1820. Epub 2011 Jan 10.
PubMed 21220605Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol. 2014 Aug 20;32(24):2541-52. doi: 10.1200/JCO.2014.55.1564.
PubMed 25071138Klepin HD. Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):8-13. doi: 10.1182/asheducation-2014.1.8. Epub 2014 Nov 18.
PubMed 25696829Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Recher C, Sandhu I, Bernal del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Dohner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. doi: 10.1182/blood-2015-01-621664. Epub 2015 May 18.
PubMed 25987659Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012 Jul;125(7 Suppl):S2-5. doi: 10.1016/j.amjmed.2012.04.014.
PubMed 22735748Platzbecker U. Treatment of MDS. Blood. 2019 Mar 7;133(10):1096-1107. doi: 10.1182/blood-2018-10-844696. Epub 2019 Jan 22.
PubMed 30670446Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
PubMed 19230772Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016 Sep;48:73-7. doi: 10.1016/j.leukres.2016.07.011. Epub 2016 Jul 22.
PubMed 27497757Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA 3rd, Doebele RC. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539.
PubMed 30624546Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221. doi: 10.1126/science.1226344. Epub 2012 Aug 23.
PubMed 22923433Ree AH, Nygaard V, Russnes HG, Heinrich D, Nygaard V, Johansen C, Bergheim IR, Hovig E, Beiske K, Negard A, Borresen-Dale AL, Flatmark K, Maelandsmo GM. Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain. Cancer Immunol Res. 2019 May;7(5):701-706. doi: 10.1158/2326-6066.CIR-18-0777. Epub 2019 Feb 25.
PubMed 30804006Von Hoff DD, Stephenson JJ Jr, Rosen P, Loesch DM, Borad MJ, Anthony S, Jameson G, Brown S, Cantafio N, Richards DA, Fitch TR, Wasserman E, Fernandez C, Green S, Sutherland W, Bittner M, Alarcon A, Mallery D, Penny R. Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010 Nov 20;28(33):4877-83. doi: 10.1200/JCO.2009.26.5983. Epub 2010 Oct 4.
PubMed 20921468Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, Long N, Schultz AR, Traer E, Abel M, Agarwal A, Blucher A, Borate U, Bryant J, Burke R, Carlos A, Carpenter R, Carroll J, Chang BH, Coblentz C, d'Almeida A, Cook R, Danilov A, Dao KT, Degnin M, Devine D, Dibb J, Edwards DK 5th, Eide CA, English I, Glover J, Henson R, Ho H, Jemal A, Johnson K, Johnson R, Junio B, Kaempf A, Leonard J, Lin C, Liu SQ, Lo P, Loriaux MM, Luty S, Macey T, MacManiman J, Martinez J, Mori M, Nelson D, Nichols C, Peters J, Ramsdill J, Rofelty A, Schuff R, Searles R, Segerdell E, Smith RL, Spurgeon SE, Sweeney T, Thapa A, Visser C, Wagner J, Watanabe-Smith K, Werth K, Wolf J, White L, Yates A, Zhang H, Cogle CR, Collins RH, Connolly DC, Deininger MW, Drusbosky L, Hourigan CS, Jordan CT, Kropf P, Lin TL, Martinez ME, Medeiros BC, Pallapati RR, Pollyea DA, Swords RT, Watts JM, Weir SJ, Wiest DL, Winters RM, McWeeney SK, Druker BJ. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018 Oct;562(7728):526-531. doi: 10.1038/s41586-018-0623-z. Epub 2018 Oct 17.
PubMed 30333627
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Precision Therapy Versus Standard Therapy in Acute Myeloid Leukaemia and Myelodysplastic Syndrome in Elderly
- ClinicalTrials.gov ID
- NCT05025098
- Acronym / sponsor ID
- PALM / PALM
- Conditions
- AML, Adult, MDS
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 36 participants (estimated)
- Lead sponsor
- University Hospital, AkershusUniversity, hospital or other
- Study start
- 22 Jun 2021 (actual)
- Primary completion
- 10 Jun 2026 (estimated)
- Study completion
- 10 Jun 2027 (estimated)
- First posted
- 27 Aug 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a randomized clinical trial that randomizes between treatment principles. The study will investigate if precision therapy determined by a tumour board is better than standard treatment for acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) in elderly. The tumour board will decide the precision therapy based on identified genetic changes that can guide customized therapy. There are currently 40-50 targeted therapies approved for various cancers in Norway. The precision therapy will be given in addition to the standard treatment.
The primary study objective will be to evaluate the cost-effectiveness of a precision therapy strategy compared with standard treatment. Other objectives will mesaure efficacy and satety of the treatment, and impact on life quality of the patients.
Detailed description
Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in the elderly are not curable since elderly patients usually do not tolerate intensive chemotherapy and allogeneic stemcell transplantation. Next generation sequencing (NGS) of DNA can find changes in tumor DNA that can be targeted by new drugs, so called "precision therapy". Precision therapy drugs are usually less toxic than standard treatment, and thus may be particularly well suited for elderly. Precision therapy is principally different from today's standard therapy since it will be individualized based on NGS from the tumor, while in standard therapy all patients receive the same treatment. It is unknown how a precision therapy strategy will perform compared with standard therapy in AML and high-risk MDS in the elderly. A Clinical Tumour Board will decide on the precision therapy.
Study design:
This is a prospective, open label, single centre, randomized phase II clinical trial. The study randomizes between standard treatment and precision therapy in unfit elderly patients with AML and high-risk MDS. Importantly, this study design is not a randomization between treatments as in a traditional clinical trial, but a randomization between treatment principles. This means that patients in the standard treatment arm will receive the same treatment, while patients in the precision arm will receive different treatments based on the profiling of the tumor cells. Since most of the precision therapies will be experimental, the study is designed so that the patients in both arms receive a period of standard treatment before randomization. This is to reduce the risk of patients not receiving effective treatment, so that the precision therapy can be tested safely. The standard treatment for AML and high-risk MDS in elderly may change during the study, therefore "standard treatment" is defined as the recommended treatment in Norway at any time point. This means that MDS patients and AML patients may have different standard therapy.
Diagnostic sampling and genomic profiling will be done on the bone marrow of all included patients before start of treatment and compared with germline DNA from buccal swab taken at the bone-marrow. Treatment with hydroxyurea prior to the initial standard treatment is allowed to get leukocytes below 30.
While the patient receive two initial 28 day cycles of standard treatment, NGS of the bone marrow samples are done and assessed in the diagnostic pipeline, followed by bioinformatics analysis. The information is then interpreted by a Clinical Tumour Board consisting of pathologists, haematologists, oncologists, molecular biologists and bioinformatician, the treating hematologist and study nurse. The Clinical Tumour Board makes the decision on targeted treatment.
After initial standard therapy bone marrow samples will be evaluated for response to treatment. Patients with progressive disease as defined by the European Leukemia Net will go out of the study and receive treatment according to investigators choice. Notably, the results from the Clinical Tumour Board will be available for these patients to provide best possible treatment.
Patients without disease progression are randomized in a stratified manner 2:1 after the initial treatment with standard therapy to either precision therapy advised by the Clinical Tumour Board or continuous standard therapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- randomized open label clinical study phase II
| Arm | Type | Receives |
|---|---|---|
| Standard therapy | Active comparator | Drug: Standard therapyThis study is a randomization between treatment principles, not treatments, i.e., standard therapy vs precision therapy (tumor board determined). Standard treatment for AML patients is Azacitidine + Venetoclax.* *Only if venetoclax is available to the study at the time-point of study start. If venetoclax is not available AML patients will receive Azacitidine alone similar to MDS patients. Standard treatment for MDS is Azacitidine. |
| Precision therapy | Experimental | Drug: Standard therapy, Drug: Precision therapyThis study is a randomization between treatment principles, not treatments, i.e., standard therapy vs precision therapy (tumor board determined). The precision therapy arm will receive standard therapy + tumor board decided precision therapy. The tumor board decided precision therapy can in principle be any therapy with marketing authorization in Norway. |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Patients with a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease and therapy-related AML (not if they have received antileukemic/mds treatment)), or
- acute leukemias of ambiguous lineage according to WHO 2016 or a diagnosis of myelodysplastic syndrome (MDS) with IPSS-R > 4.5.1
- Patients 60 years and older.
- Patients must NOT be eligible for intensive chemotherapy or allogeneic stem cell therapy (See Chapter 23.3)
- WBC ≤ 25 x109/L (prior hydroxyurea allowed for a maximum of 14 days, stopped before start of treatment)
Key exclusion criteria (23 listed)
- Acute promyelocytic leukemia.
- AML with favourable cytogenetic or genetic changes in patients who are fit for intensive chemotherapy. Favourable genetics are: t(8;21)(q22;q22.1); RUNX1-RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†; Biallelic mutated CEBPA
- Patients previously treated for AML or MDS (any antileukemic therapy or MDS treatment including investigational agents).
- Patients where it is not possible to get bone-marrow for NGS, i.e., "dry tap".
- Diagnosis of any previous or concomitant malignancy is an exclusion criterion: except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Standard therapyAlso: Azacitidine + venetoclax for AML patients. Azacitidine for MDS patients.For AML patients: Venetoclax will be administered orally once daily Days 1 through 28, of a 28-day cycle, with a designated dose of 400 mg daily after ramp up in Cycle 1. During Cycle 1 Days 1 - 3, the dose of Venetoclax will ramp up from 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3. Azacitidine (100 mg/m2) is given once daily following administration of venetoclax for 5 days of every cycle, starting on Day 1 of each cycle. For MDS patients: Azacitidine (100 mg/m2) is given once daily for 5 days of every 28 day cycle, starting on day 1 of each cycle. | Drug | Precision therapy, Standard therapy |
| Precision therapyAlso: Standard therapy + tumor board decided precision therapy drug.Precision therapy for both AML and MDS patients is standard therapy + tumor board determined precision therapy. The tumor board determined precision therapy can be all available drugs with a marketing authorization in Norway. | Drug | Precision therapy |
Primary outcome
cost-effectiveness of a precision therapy
Time frame: 4-5 years
To evaluate the cost-effectiveness of a precision therapy strategy compared with standard treatment. The total cost of the treatment will be calculated and divided on health related quality of life (HRQoL)
16 secondary outcomes
Event free survival
Time frame: 4-5 years
Overall survival
Time frame: 4-5 years
Adverse events
Time frame: 4-5 years
Toxicity
Time frame: 4-5 years
Transfusion independence
Time frame: 4-5 years
Budget impact
Time frame: 4-5 years
Overall response rate
Time frame: 4-5 years
Quality of life
Time frame: 4-5 years
Total costs
Time frame: 4-5 years
Progression
Time frame: 4-5 years
Sequencing quality
Time frame: 4-5 years
Dry tap
Time frame: 4-5 years
Person staff time
Time frame: 4-5 years
Person-time used to find possible precision therapy
Time frame: 4-5 years
Patients with actionable targets
Time frame: 4-5 years
MDS progression to AML
Time frame: 4-5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2021.
- Background: PubMed 27335276Pfeilstocker M, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Levis A, Luebbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SM, Miyazaki Y, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016 Aug 18;128(7):902-10. doi: 10.1182/blood-2016-02-700054. Epub 2016 Jun 22.
- Background: PubMed 19776405Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Dohner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. doi: 10.1056/NEJMoa0901409.
- Background: PubMed 21220605Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011 Feb 10;29(5):487-94. doi: 10.1200/JCO.2010.30.1820. Epub 2011 Jan 10.
- Background: PubMed 25071138Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol. 2014 Aug 20;32(24):2541-52. doi: 10.1200/JCO.2014.55.1564.
- Background: PubMed 25696829Klepin HD. Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):8-13. doi: 10.1182/asheducation-2014.1.8. Epub 2014 Nov 18.
- Background: PubMed 25987659Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Recher C, Sandhu I, Bernal del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Dohner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. doi: 10.1182/blood-2015-01-621664. Epub 2015 May 18.
- Background: PubMed 22735748Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012 Jul;125(7 Suppl):S2-5. doi: 10.1016/j.amjmed.2012.04.014.
- Background: PubMed 30670446Platzbecker U. Treatment of MDS. Blood. 2019 Mar 7;133(10):1096-1107. doi: 10.1182/blood-2018-10-844696. Epub 2019 Jan 22.
- Background: PubMed 19230772Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
- Background: PubMed 27497757Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016 Sep;48:73-7. doi: 10.1016/j.leukres.2016.07.011. Epub 2016 Jul 22.
- Background: PubMed 30624546Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA 3rd, Doebele RC. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539.
- Background: PubMed 22923433Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221. doi: 10.1126/science.1226344. Epub 2012 Aug 23.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Anders Erik Astrup Dahm, MD, PHD principal investigator
Akershus universitetssykehus
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Standard therapy and Precision therapy in people with AML, Adult and MDS, run by University Hospital, Akershus at 1 site in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anders Erik Astrup Dahm, MD,PHD (+4793059809, aeadahm@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
cost-effectiveness of a precision therapy (time frame: 4-5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05025098, which also lists 33 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2021.