MYELOMATCH: A Screening Study to Assign People With Myeloid Cancer to a Treatment Study or Standard of Care Treatment Within myeloMATCH (MyeloMATCH Screening Trial)
Purpose
This MyeloMATCH Master Screening and Reassessment Protocol (MSRP) evaluates the use of a screening tool and specific laboratory tests to help improve participants' ability to register to clinical trials throughout the course of their myeloid cancer (acute myeloid leukemia or myelodysplastic syndrome) treatment. This study involves testing patients' bone marrow and blood for certain biomarkers. A biomarker (sometimes called a marker) is any molecule in the body that can be measured. Doctors look at markers to learn what is happening in the body. Knowing about certain markers can give doctors more information about what is driving the cancer and how to treat it. Testing patients' bone marrow and blood will show doctors if patients have markers that specific drugs can target. The marker testing in this study will let doctors know if they can match patients with a treatment study (myeloMATCH clinical trial) that tests treatment for the type of cancer they have or continue standard of care treatment with their doctor on the Tier Advancement Pathway (TAP).
Conditions
- Acute Myeloid Leukemia
- Myelodysplastic Syndrome
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- Participants must be suspected to have previously untreated acute myeloid leukemia
(AML) or myelodysplastic syndrome (MDS). Participants with AML cannot have a history
of previously treated myeloproliferative neoplasms (MPN) or MDS.
- Participants must be >= 18 years of age.
- Participants must not have received prior anti-cancer therapy for AML or MDS.
- Note: Hydroxyurea to control the white blood cell count (WBC) is allowed.
- Note: Prior erythroid stimulating agent (ESA) is not considered prior therapy
for the purposes of eligibility. Participants must not be currently receiving
any cytarabine-containing therapy other than up to 1 g/m^2 of cytarabine, which
is allowed for urgent cytoreduction.
- Participants are allowed prior use of hydroxyurea, all-trans retinoic acid (ATRA),
BCR-ABL directed tyrosine kinase inhibitor, erythropoiesis-stimulating agent,
thrombopoietin receptor agonist and lenalidomide, with a maximum limit of 1 month of
exposure.
- Note: Participants receiving hydroxyurea prior to treatment substudy or TAP
assignment must agree to discontinue hydroxyurea within 24 hours before
beginning substudy or TAP treatment.
- Participants must not have a prior or concurrent malignancy that requires concurrent
anti-cancer therapy
- Note: active hormonal therapy is allowed
- Participants must have a Zubrod Performance Status evaluation within 28 days prior
to registration.
- Participants must agree to have translational medicine specimens submitted.
- Participants must be offered the opportunity to participate in specimen banking.
- Note: Specimens must be collected and submitted following the initial
paper-based process and subsequently via the Precision Medicine Specimen
Tracking Forms in Medidata Rave instance for the MyeloMATCH MSRP.
- Participants must be informed of the investigational nature of this study and must
sign and give informed consent in accordance with institutional and federal
guidelines.
- Note: As a part of the Oncology Patient Enrollment Network (OPEN) registration
process the treating institution's identity is provided in order to ensure that
the current (within 365 days) date of institutional review board approval for
this study has been entered in the system.
- The master screening and reassessment protocol (MSRP) should only be used in sites
where the relevant AML treatment substudies are open or if the site is willing to
follow the MSRP Tier Advancement Pathway (TAP) for patients in the event that the
site does not have the relevant study open and transfer to another site that does
have the study open. For example, if a site does not have a myeloMATCH Tier 1 study
for older AML open for enrollment, such older AML patients should only be consented
for the MSRP if the site is willing to treat the patient with standard of care on
TAP or is willing to transfer the patient to a center with a study open that the
patient would otherwise match to.
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- N/A
- Intervention Model
- Single Group Assignment
- Primary Purpose
- Screening
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator MM1MDS-A01 Arm A (ASTX727) |
Patients receive ASTX727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or stable disease (SD) any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. |
|
|
Experimental MM1MDS-A01 Arm B (ASTX727, enasidenib) |
Patients receive ASTX727 PO QD on days 1-5 and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. |
|
|
Experimental MM1OA-EA02 Regimen 1 (azacitidine, venetoclax) |
INDUCTION: Patients receive azacitidine IV or SC on days 1-7 of each cycle and venetoclax PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial. |
|
|
Experimental MM1OA-EA02 Regimen 2 (azacitidine, venetoclax, gilteritinib) |
INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial. |
|
|
Experimental MM1OA-EA02 Regimen 3 (azacitidine, venetoclax, gilteritinib) |
INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial. |
|
|
Active Comparator MM1OA-S03 Arm 1 (ASTX727, venetoclax) |
Patients receive ASTX727 PO QD on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. |
|
|
Experimental MM1OA-S03 Arm 2 (ASTX727, venetoclax, enasidenib) |
Patients receive ASTX727 PO QD on days 1-5, venetoclax PO QD on days 1-28, and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. |
|
|
Experimental MM1YA-CTG01 Arm I (daunorubicin, cytarabine, venetoclax) |
Patients receive daunorubicin IV, cytarabine IV, and venetoclax PO on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. |
|
|
Experimental MM1YA-CTG01 Arm II (azacitidine, venetoclax) |
Patients receive azacitidine IV or SC and venetoclax PO on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. |
|
|
Active Comparator MM1YA-CTG01 Arm III (daunorubicin, cytarabine) |
Patients receive daunorubicin IV and cytarabine IV on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. |
|
|
Active Comparator MM1YA-S01 Arm I (cytarabine, daunorubicin) |
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. |
|
|
Experimental MM1YA-S01 Arm II (cytarabine, daunorubicin, venetoclax) |
Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. |
|
|
Experimental MM1YA-S01 Arm III (azacitidine, venetoclax) |
Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. |
|
|
Experimental MM1YA-S01 Arm IV (Vyxeos) |
Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. |
|
|
Experimental MM1YA-S01 Arm V (Vyxeos, venetoclax) |
Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. |
|
|
Active Comparator MM2YA-EA01 Arm A (cytarabine) |
Patients receive cytarabine IV on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. |
|
|
Experimental MM2YA-EA01 Arm B (cytarabine, venetoclax) |
Patients receive cytarabine IV and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. |
|
|
Experimental MM2YA-EA01 Arm C (Vyxeos, venetoclax) |
Patients receive Vyxeos IV and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. |
|
|
Experimental MM2YA-EA01 Arm D (azacitidine, venetoclax) |
Patients receive azacitidine IV or SC and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. |
|
|
Experimental Screening (mutation carrier screening) |
Patients undergo bone marrow aspiration and collection of blood on study. Patients' bone marrow and blood specimens undergo rapid genetic testing. Patients are then assigned to a specific substudy containing a therapy targeted to the patient's mutational profile. If there is no targetable mutation, the patient is placed on a substudy testing novel combinations that do not contain a target-specific drug. Patients who are not eligible for any MYELOMATCH substudy are assigned to TAP. |
|
|
Experimental TAP (SOC treatment, mutation carrier screening) |
Patients continue SOC treatment and undergo continued bone marrow aspiration and blood collection for possible future substudy assignment. |
|
Recruiting Locations
Birmingham, Alabama 35233
Tucson, Arizona 85719
Tucson, Arizona 85719
Little Rock, Arkansas 72205
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501-686-8274
Long Beach, California 90822
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562-826-8000
Los Angeles, California 90048
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310-423-8965
Sacramento, California 95817
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916-734-3089
New Haven, Connecticut 06520
West Haven, Connecticut 06516
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203-937-3421
Augusta, Georgia 30912
Boise, Idaho 83706
Boise, Idaho 83712
Caldwell, Idaho 83605
Coeur d'Alene, Idaho 83814
Fruitland, Idaho 83619
Meridian, Idaho 83642
Nampa, Idaho 83687
Nampa, Idaho 83687
Post Falls, Idaho 83854
Sandpoint, Idaho 83864
Bloomington, Illinois 61701
Bloomington, Illinois 61704
Canton, Illinois 61520
Carthage, Illinois 62321
Chicago, Illinois 60611
Chicago, Illinois 60637
Danville, Illinois 61832
Decatur, Illinois 62526
Decatur, Illinois 62526
DeKalb, Illinois 60115
Dixon, Illinois 61021
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815-285-7800
Effingham, Illinois 62401
Effingham, Illinois 62401
Eureka, Illinois 61530
Evanston, Illinois 60201
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847-570-2109
Galesburg, Illinois 61401
Geneva, Illinois 60134
Glenview, Illinois 60026
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847-570-2109
Glenview, Illinois 60026
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312-695-1102
Grayslake, Illinois 60030
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312-695-1102
Highland Park, Illinois 60035
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847-570-2109
Kewanee, Illinois 61443
Lake Forest, Illinois 60045
Macomb, Illinois 61455
Mattoon, Illinois 61938
Maywood, Illinois 60153
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708-226-4357
O'Fallon, Illinois 62269
Orland Park, Illinois 60462
Ottawa, Illinois 61350
Pekin, Illinois 61554
Peoria, Illinois 61615
Peoria, Illinois 61636
Peoria, Illinois 61637
Peru, Illinois 61354
Princeton, Illinois 61356
Springfield, Illinois 62702
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217-545-7929
Springfield, Illinois 62702
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800-444-7541
Springfield, Illinois 62781
Urbana, Illinois 61801
Warrenville, Illinois 60555
Washington, Illinois 61571
Indianapolis, Indiana 46202
Des Moines, Iowa 50314
Iowa City, Iowa 52242
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800-237-1225
Fairway, Kansas 66205
Hays, Kansas 67601
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785-623-5774
Kansas City, Kansas 66160
Lawrence, Kansas 66044
Olathe, Kansas 66061
Overland Park, Kansas 66210
Overland Park, Kansas 66211
Salina, Kansas 67401
Topeka, Kansas 66606
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785-270-4939
Topeka, Kansas 66606
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785-295-8000
Westwood, Kansas 66205
Lexington, Kentucky 40536
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859-257-3379
Baton Rouge, Louisiana 70805
Baton Rouge, Louisiana 70808
Baton Rouge, Louisiana 70808
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225-765-7659
Brunswick, Maine 04011
South Portland, Maine 04106
Baltimore, Maryland 21287
Boston, Massachusetts 02111
Ann Arbor, Michigan 48106
Brighton, Michigan 48114
Canton, Michigan 48188
Chelsea, Michigan 48118
Detroit, Michigan 48201
Detroit, Michigan 48202
Farmington Hills, Michigan 48334
Flint, Michigan 48503
Flint, Michigan 48503
Flint, Michigan 48503
Flint, Michigan 48503
Livonia, Michigan 48154
Novi, Michigan 48377
West Bloomfield, Michigan 48322
Ypsilanti, Michigan 48197
Deer River, Minnesota 56636
Duluth, Minnesota 55805
Edina, Minnesota 55435
Hibbing, Minnesota 55746
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218-786-3308
Minneapolis, Minnesota 55407
Saint Louis Park, Minnesota 55416
Saint Paul, Minnesota 55102
Virginia, Minnesota 55792
Columbus, Mississippi 39705
Grenada, Mississippi 38901
New Albany, Mississippi 38652
Oxford, Mississippi 38655
Southhaven, Mississippi 38671
Creve Coeur, Missouri 63141
Kansas City, Missouri 64108
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816-404-4375
Kansas City, Missouri 64154
Lee's Summit, Missouri 64064
Saint Joseph, Missouri 64506
Saint Louis, Missouri 63110
Saint Louis, Missouri 63128
Saint Louis, Missouri 63129
Saint Louis, Missouri 63136
Saint Peters, Missouri 63376
Billings, Montana 59101
Bozeman, Montana 59715
Great Falls, Montana 59405
Kalispell, Montana 59901
Missoula, Montana 59802
Missoula, Montana 59804
Bellevue, Nebraska 68123
Omaha, Nebraska 68118
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402-559-5600
Omaha, Nebraska 68198
Henderson, Nevada 89052
Las Vegas, Nevada 89102
Las Vegas, Nevada 89148
Basking Ridge, New Jersey 07920
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212-639-7592
Livingston, New Jersey 07039
Long Branch, New Jersey 07740
Middletown, New Jersey 07748
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Montvale, New Jersey 07645
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New Brunswick, New Jersey 08903
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732-235-7356
Toms River, New Jersey 08755
Albuquerque, New Mexico 87106
Bronx, New York 10467
Commack, New York 11725
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212-639-7592
Lake Success, New York 11042
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516-734-8896
Manhasset, New York 11030
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516-734-8896
New York, New York 10029
New York, New York 10065
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212-639-7592
Rochester, New York 14621
Rochester, New York 14642
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585-275-5830
Syracuse, New York 13210
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315-464-5476
Uniondale, New York 11553
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212-639-7592
Chapel Hill, North Carolina 27599
Durham, North Carolina 27710
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888-275-3853
Winston-Salem, North Carolina 27103
Winston-Salem, North Carolina 27157
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336-713-6771
Cleveland, Ohio 44106
Columbus, Ohio 43210
Oklahoma City, Oklahoma 73104
Newberg, Oregon 97132
Ontario, Oregon 97914
Oregon City, Oregon 97045
Portland, Oregon 97213
Portland, Oregon 97225
Portland, Oregon 97239
Allentown, Pennsylvania 18103
Danville, Pennsylvania 17822
Philadelphia, Pennsylvania 19104
Philadelphia, Pennsylvania 19107
Pittsburgh, Pennsylvania 15232
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412-647-8073
West Reading, Pennsylvania 19611
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610-988-9323
Wilkes-Barre, Pennsylvania 18711
Providence, Rhode Island 02903
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401-444-1488
Boiling Springs, South Carolina 29316
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864-241-6251
Easley, South Carolina 29640
Greenville, South Carolina 29605
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864-241-6251
Greenville, South Carolina 29605
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864-241-6251
Greenville, South Carolina 29615
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864-241-6251
Greer, South Carolina 29650
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864-241-6251
Seneca, South Carolina 29672
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864-241-6251
Sioux Falls, South Dakota 57104
Sioux Falls, South Dakota 57117-5134
Collierville, Tennessee 38017
Memphis, Tennessee 38120
Salt Lake City, Utah 84112
Salt Lake City, Utah 84148
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801-582-1565
Charlottesville, Virginia 22908
Fairfax, Virginia 22031
Falls Church, Virginia 22042
Richmond, Virginia 23298
Edmonds, Washington 98026
Issaquah, Washington 98029
Seattle, Washington 98122
Appleton, Wisconsin 54911
Ashland, Wisconsin 54806
Burlington, Wisconsin 53105
Cudahy, Wisconsin 53110
Eau Claire, Wisconsin 54701
Germantown, Wisconsin 53022
Grafton, Wisconsin 53024
Green Bay, Wisconsin 54301
Green Bay, Wisconsin 54303
Green Bay, Wisconsin 54311
Kenosha, Wisconsin 53142
La Crosse, Wisconsin 54601
Madison, Wisconsin 53705
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608-256-1901
Madison, Wisconsin 53718
Madison, Wisconsin 53792
Marinette, Wisconsin 54143
Marshfield, Wisconsin 54449
Milwaukee, Wisconsin 53209
Milwaukee, Wisconsin 53215
Milwaukee, Wisconsin 53226
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414-805-3666
Milwaukee, Wisconsin 53233
Minocqua, Wisconsin 54548
Mukwonago, Wisconsin 53149
Oconomowoc, Wisconsin 53066
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262-928-7878
Oconto Falls, Wisconsin 54154
Oshkosh, Wisconsin 54904
Racine, Wisconsin 53406
Rice Lake, Wisconsin 54868
Sheboygan, Wisconsin 53081
Sheboygan, Wisconsin 53081
Stevens Point, Wisconsin 54482
Sturgeon Bay, Wisconsin 54235-1495
Summit, Wisconsin 53066
Two Rivers, Wisconsin 54241
Waukesha, Wisconsin 53188
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262-928-7632
Waukesha, Wisconsin 53188
Wauwatosa, Wisconsin 53226
West Allis, Wisconsin 53227
Weston, Wisconsin 54476
San Juan, Puerto Rico 00927
San Juan, Puerto Rico 00936
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787-763-1296
More Details
- NCT ID
- NCT05564390
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Detailed Description
PRIMARY OBJECTIVES: I. Screening and Reassessment (MSRP): To evaluate the feasibility of MATCHBox receiving and organizing all data needed for assignment to a myeloMATCH clinical trial or Tier Advancement Pathway (TAP) within 72 hours of MDNet receipt of all required specimens for initial therapy and within 10 days for subsequent therapy. II. Tier Advancement Pathway (TAP): To enable participants who are not matched to an investigational myeloMATCH treatment substudy to receive standard of care (SOC) while remaining on the MSRP to maintain access to later tiers of treatment substudies. SECONDARY OBJECTIVES: I. Screening and Reassessment (MSRP): Ia. To describe the time to generation of all data required for treatment substudy (or TAP) assignment, time to treatment substudy (or TAP) assignment, percent assigned to a myeloMATCH treatment substudy, and the percent of screened participants who register to a myeloMATCH investigational treatment substudy or are assigned to TAP: Iai. Separately within each tier of myeloMATCH treatment substudy and analogous TAP assignment; Ibi. Separately within each clinical basket of myeloMATCH treatment substudies; Ici. Over time, across and within the categories above. II. Tier Advancement Pathway (TAP): IIa. To evaluate participants for assignment to higher tier treatment substudies within myeloMATCH; IIb. To describe, within tier- and basket- levels of TAP, measurable residual disease (MRD) rates and clonal evolution; IIc. To describe, within tier- and basket- levels of TAP, remission status and overall survival of participants who receive standard of care therapy; IId. To obtain MDNet specimens for translational medicine and biobanking. OUTLINE: REGISTRATION: Patients undergo bone marrow aspiration and collection of blood on study. Patients' bone marrow and blood specimens undergo rapid genetic testing. Patients are then assigned to a specific substudy containing a therapy targeted to the patient's mutational profile. If there is no targetable mutation, the patient is placed on a substudy testing novel combinations that do not contain a target-specific drug. Patients who are not eligible for any MYELOMATCH substudy are assigned to TAP. TAP: Patients continue SOC treatment and undergo continued bone marrow aspiration and blood collection for possible future substudy assignment. TREATMENT: Patients are assigned to a specific treatment substudy. MM1YA-CTG01: Younger patients (age 18-59 years) with intermediate risk acute myeloid leukemia (AML) are randomized to 1 of 3 arms. ARM I: Patients receive daunorubicin intravenously (IV), cytarabine IV, and venetoclax orally (PO) on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. ARM II: Patients receive azacitidine IV or subcutaneously (SC) and venetoclax PO on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. ARM III: Patients receive daunorubicin IV and cytarabine IV on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. MM1YA-S01: Younger patients (age 18-59 years) with high-risk AML are randomized to 1 of 5 arms. ARM I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. ARM II: Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. ARM III: Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. ARM IV: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. MM2YA-EA01: Younger patients (age 18-59 years) with AML or secondary AML who have completed a tier 1 MyeloMATCH treatment study with complete remission (CR) or CR with partial hematologic recovery (CRh) and have detectable minimal residual disease (MRD) (> 0.1%) are randomized to 1 of 4 arms. ARM A: Patients receive cytarabine IV on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. ARM B: Patients receive cytarabine IV and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. ARM C: Patients receive Vyxeos IV and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. ARM D: Patients receive azacitidine IV or SC and venetoclax PO on study. Patients undergo bone marrow aspiration and biopsy on study. Patients may also undergo ECHO and/or MUGA as clinically indicated. MM1OA-EA02: Patients are randomized to 1 of 3 regimens. REGIMEN 1: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 2: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 3: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. MM1MDS-A01: Patients are randomized to 1 of 2 arms. ARM A: Patients receive ASTX727 PO once daily (QD) on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR, CRL, or CRh at the end of cycle 6 may cross-over to Arm B. Patients who experience CR, PR, or stable disease (SD) any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. ARM B: Patients receive ASTX727 PO QD on days 1-5 and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience CR, PR, or SD any time after 4 cycles of treatment may be reassessed in order to go to a higher myeloMATCH tier assignment or to TAP. Patients also undergo bone marrow biopsy and aspiration throughout the study. Patients may also undergo optional buccal swab on study, and/or optional additional bone marrow aspiration and blood sample collection on study and at disease progression. MM1OA-S03: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive ASTX727 PO QD on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. ARM 2: Patients receive ASTX727 PO QD on days 1-5, venetoclax PO QD on days 1-28, and enasidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration, and bone marrow biopsy throughout the trial. All patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.