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Table 5 Ongoing clinical trials evaluating PARPi in acute leukemia, together with patient population, relevant inclusion criteria that may drive future clinical development, preliminary results

From: Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

NCT ID

NCT03953898

NCT02878785

NCT03974217

NCT01399840

NCT01139970

NCT00588991

NCT03289910

NCT04207190

Title

Using the Anticancer Drug Olaparib to Treat R/R AML or MDS With an IDH Mutation

Decitabine and Talazoparib in Untreated AML and R/R AML (1565GCC)

Talazoparib for Cohesin-Mutated AML and MDS With Excess Blasts

Study of BMN 673, a PARP Inhibitor, in Patients With Advanced Hematological Malignancies [172]

Veliparib and Temozolomide in Treating Patients With Acute Leukemia [160]

Veliparib and Topotecan W/Wo Carboplatin in Treating Patients With R/R Acute Leukemia, High-Risk MDS, or Aggressive MPDs

Topotecan Hydrochloride and Carboplatin W/Wo Veliparib in Treating Advanced MPDs and AML or CML [161]

Talazoparib and GO for the Treatment of CD33+ R/R AML

Phase

2

1

2

1

1

1

2

1/2

Number of pts

94

171

12

33

66

12

60

20

Drug and schedule

Olaparib PO BID

Sequential dose escalation of decitabine and talazoparib, 3 + 3 design

Talazoparib, allowed HU

BMN 673

Veliparib PO once daily QD on d 1–4 and twice daily on d 4–12 and temozolomide PO QD on d 3–9 of course 1. Beginning at least 30 d after the start of treatment, pts receive veliparib PO BID on d 1–8 and temozolomide PO QD on d 1–5. Courses. dose escalated

Veliparib when given together with topotecan hydrochloride w/wo carboplatin, doses escalated

ARM A: veliparib orally (PO) twice daily (BID) on days 1–21 and topotecan hydrochloride IV continuously over 24 h and carboplatin IV continuously over 24 h on d 3–7 ARM B: no veliparib

Pts receive talazoparib PO daily on d 1–21 and GO IV over 2 h on d 1, 4, and 7 or d 1 for pts at CR/CRi after cycles 1 or 2. Dose escalated

Population

R/R AML

R/R AML in phase 1, new diagnosis AML unfit phase 2

R/R AML, secondary AML or R/R MDS RAEB after aza

AML, MDS, CLL, MCL

R/R AML, R/R b-ALL, CML in accelerated/blast phase after 2 TKI, CMML-2, new onset high-risk AML > 60 y, new onset high-risk ALL > 60 y

Aggressive MPD or AML out of MPD

New onset AML secondary to MPD, R/R AML secondary to MPD, accelerated phase MPD

R/R AML

Genetics

IDH1/2 mut

No

Cohesin mut (STAG2, SMC1A, RAD21, PDS5B, SMC3)

No

No

No

No

CD33 > 0.1%

Endpoint

ORR

Safe dose phase 1, CR + CRi phase 2

> 50% blast reduction

MTD

MTD

MTD

ORR

MTD phase 1; ORR extension

Exclusion for cytopenia

No

No

No

BM cellularity < 25% for AML; MCL and CLL: platelet count < 50.000/mm3, neutrophil count < 1.000/mm3

No

No

No

No

Previous sct excluded

No

No

No

No

No

No

No

No

Exclusion for hyperleuko cytosis

> 50.000

> 50.000

> 10.000

> 50.000

> 30.000

> 50.000

No

No

Corrected QT exclusion criteria

> 500

No

No

No

No

No

No

No

Strong CYP3A4 inhibitor

Yes

No

No

No

No

No

No

No

Safety profile for future development

Nr

Nr

Nr

Suitable

Suitable

Nr

Suitable

Nr

Efficacy results

Nr

Nr

Nr

Stable disease in 12/24 pts. AML/MDS, 1 MDS pt. transfusion indpt

CR + CRi 16.6% (8/48); median OS = 5.3 m

Nr

ORR = 33% (14 CR, 11 CRi)

Nr

  1. ALL: acute lymphoblastic leukemia, AML: acute myeloid leukemia, aza: 5-azacytidine, BID: bis per die, BM: bone marrow, CLL: chronic lymphocytic leukemia, CML: chronic myeloid leukemia, CMML: chronic myelomonocytic leukemia, CR: complete remission, CRi: complete remission with incomplete hematological recovery, d: days, h: hours, HU: hydroxyurea indpt; independence, IV: intravenously, m: months, MCL: mantle cell lymphoma. MDS: myelodysplastic syndrome, MPD: myeloproliferative disorder, MTD: maximum tolerated dose, mut: mutation, nr: not reported, ORR: overall response rate, PO: per os, pts: patients, QD: quadam per die, RAEB: refractory anemia with excess blasts, R/R: relapsed/refractory; sct: stem cell transplantation, w/wo: with or without, y: years