Table 3 Summary of DNA methylation-targeted drugs for different diseases in clinical trials

DNMT inhibitor

Guadecitabine

DNMT1

Platinum refractory germ cell cancer

Completed (exhibits tolerable safety and satisfied activity)

Phase I

In combination with Cisplatin

NCT02429466¹⁰¹³

Guadecitabine

DNMT1

Liver cancer, pancreatic cancer, bile duct cancer, gallbladder cancer

Active, not recruiting

Phase I

In combination with Durvalumab

NCT03257761

Guadecitabine

DNMT1

Lung cancer

Active, not recruiting

Phase I

In combination with Pembrolizumab and Mocetinostat

NCT03220477

Guadecitabine

DNMT1

AML

Completed (exhibits an overall unfavorable benefit-risk profile at the investigated dose levels)

Phase I

In combination with Atezolizumab

NCT02892318²⁷⁶

Guadecitabine

DNMT1

Colorectal cancer

Completed (no significant clinical activity of the Guadecitabine with Cy/GVAX is observed)

Phase I

CY/GVAX (active comparator/followed by Guadecitabine)

NCT01966289²⁷⁷

Guadecitabine

DNMT1

Castration-resistant prostatic cancer, NSCLC

Recruiting (helps to reverse resistance to immune checkpoint inhibitors according to early clinical data)

Phase I

ASTX727 (active comparator); in combination with Pembrolizumab

NCT02998567¹⁰¹⁴

Guadecitabine

DNMT1

AML

Completed (subcutaneous administration of large doses may be beneficial for improving treatment efficacy while increases the risk of adverse events)

Phase I

—

NCT02293993

Guadecitabine

DNMT1

Melanoma

Completed (helps to achieve long-term clinical benefits)

Phase I

In combination with Ipilimumab

NCT02608437^281,282

Guadecitabine

DNMT1

SCLC

Completed (unpublished)

Phase I

In combination with platinum-based first-line chemotherapy, Durvalumab, and Tremelimumab

NCT03085849

Guadecitabine

DNMT1

AML, MDS

Terminated (not due to patient safety)

Phase II

—

NCT03603964

Guadecitabine

DNMT1

MDS

Active, not recruiting

Phase II

—

NCT02131597

Guadecitabine

DNMT1

AML, MDS

Unknown

Phase II

ASCT

NCT03454984

Guadecitabine

DNMT1

Paraganglioma, GIST, RCC, pheochromocytoma

Terminated (exhibits manageable toxicity with low objective response rates)

Phase II

—

NCT03165721²⁷⁸

Guadecitabine

DNMT1

SCLC

Completed (exhibits good efficacy but with the possibility of adverse events)

Phase II

In combination with Cisplatin

NCT03913455¹⁰¹⁵

Guadecitabine

DNMT1

Urothelial carcinoma

Active, not recruiting (possibly prolongs patient survival)

Phase II

In combination with Atezolizumab

NCT03179943¹⁰¹⁶

Guadecitabine

DNMT1

Philadelphia-negative myeloproliferative neoplasms

Completed (helps improve quality of life and exhibits acceptable adverse events)

Phase II

—

NCT03075826

Guadecitabine

DNMT1

HCC

Completed (high incidence of treatment-related adverse events)

Phase II

—

NCT01752933

Guadecitabine

DNMT1

AML

Completed (exhibits comparable clinical response rates and safety)

Phase II

With or without Cladribine or Idarubicin

NCT02096055

Guadecitabine

DNMT1

Fallopian tube carcinoma, peritoneal carcinoma

Completed (exhibits clinical benefit and possibly activates antitumor immunity)

Phase II

In combination with Pembrolizumab

NCT02901899¹⁰¹⁷

Guadecitabine

DNMT1

MDS

Completed (exhibits potential therapeutic effects on high-risk patients who failed azacitidine)

Phase II

—

NCT02197676¹⁰¹⁸

Guadecitabine

DNMT1

AML, CMML, MDS

Active, not recruiting

Phase II

In combination with donor lymphocytes

NCT02684162

Guadecitabine

DNMT1

Melanoma, NSCLC

Not yet recruiting

Phase II

With or without Ipilimumab plus Nivolumab

NCT04250246

Guadecitabine

DNMT1

Central chondrosarcoma

Active, not recruiting

Phase II

In combination with Belinostat or ASTX727

NCT04340843¹⁰¹⁹

Guadecitabine

DNMT1

Ovarian cancer

Completed (helps to increase progression-free survival within six months)

Phase II

In combination with Carboplatin

NCT01696032¹⁰²⁰

Guadecitabine

DNMT1

Colorectal cancer

Withdrawn (due to the insufficient funding)

Phase I/II

In combination with Nivolumab

NCT03576963

Guadecitabine

DNMT1

RCC

Active, not recruiting (exhibits satisfied safety and tolerability)

Phase I/II

In combination with Durvalumab

NCT03308396¹⁰²¹

Guadecitabine

DNMT1

AML, MDS, CMML

Active, not recruiting (exhibits manageable adverse events and typical cytopenia-related safety concerns)

Phase I/II

In combination with Atezolizumab

NCT02935361¹⁰²²

Guadecitabine

DNMT1

AML, MDS, CMML

Completed (exhibits well clinically active and acceptable tolerability)

Phase I/II

—

NCT01261312^{1023,1024,1025,1026}

Guadecitabine

DNMT1

Colorectal cancer

Completed (exhibits comparable efficacy and safety profiles)

Phase I/II

In combination with Irinotecan; Regorafenib or TAS-102 (active comparator)

NCT01896856^280,1027

Guadecitabine

DNMT1

Platinum-resistant fallopian tube carcinoma, platinum-resistant ovarian carcinoma, platinum-resistant primary peritoneal carcinoma

Active, not recruiting

Phase I/II

Atezolizumab (active comparator/followed by Guadecitabine); with or without CDX-1401 vaccine

NCT03206047

Guadecitabine

DNMT1

MDS, CMML

Completed (exhibits comparable therapeutic effects and safety profiles)

Phase III

Low-dose Cytarabine/standard IC/BSC (active comparator)

NCT02907359

Guadecitabine

DNMT1

AML

Completed (exhibits higher clinical response rates and comparable safety)

Phase III

High-dose Cytarabine/low-dose Cytarabine/BSC(active comparator)

NCT02920008²⁷⁹

Guadecitabine

DNMT1

AML

Completed (no significant clinical activity of the Guadecitabine and active comparators is observed)

Phase III

Low-dose Cytarabine/high-dose Cytarabine (active comparator)

NCT02348489²⁸³

MG98

DNMT1

Solid tumors

Completed (exhibits early evidence of clinical activity with good tolerability)

Phase I

—

NCT00003890²⁹⁷

MG98

DNMT1

Metastatic renal carcinoma

Terminated (exhibits no antitumor activities)

Phase II

—

²⁹⁸

Hydralazine

DNMT1/3a/3b

Lung cancer

Completed (unpublished)

Phase I

In combination with Valproic acid

NCT00996060

Hydralazine

DNMT1/3a/3b

Refractory solid tumors

Completed (exhibits the potential to overcome chemotherapy resistance)

Phase II

In combination with Magnesium valproate

NCT00404508³⁰⁴

Hydralazine

DNMT1/3a/3b

Cervical cancer

Completed (unpublished)

Phase II

In combination with Magnesium valproate and Cisplatin chemoradiation

NCT00404326

Hydralazine

DNMT1/3a/3b

BC

Terminated (treatment is well-tolerated)

Phase II

In combination with Magnesium valproate

NCT00395655³⁰¹

Hydralazine

DNMT1/3a/3b

HCC

Completed (exhibits good efficacy and manageable toxicities)

Phase II

In combination with Valproic acid

TPVGH97-07-07¹⁰²⁸

Hydralazine

DNMT1/3a/3b

MDS

Unknown

Phase II

In combination with Valproic acid; BSC (active comparator)

NCT01356875

Hydralazine

DNMT1/3a/3b

BC

Withdrawn (IRB request)

Phase I/II

—

NCT00575978

Hydralazine

DNMT1/3a/3b

Rectal cancer

Withdrawn (No enrollment)

Phase I/II

—

NCT00575640

Hydralazine

DNMT1/3a/3b

Ovarian cancer

Unknown

Phase III

In combination with Magnesium valproate; placebo-controlled

NCT00533299

Hydralazine

DNMT1/3a/3b

Cervical cancer

Completed (exhibits advantages in progression-free survival)

Phase III

In combination with Magnesium valproate; placebo-controlled

NCT00532818

Hydralazine

DNMT1/3a/3b

Cervical cancer

Unknown

Phase III

In combination with Magnesium valproate, Carboplatin, and Paclitaxel; placebo-controlled

NCT02446652

TET agonist

Vitamin C/Ascorbate

TET1//2/3

MDS, AML

Completed (enhances the biological effects of DNMT inhibitors)

Pilot trial

In combination with Azacitidine

NCT02877277³³⁵

Vitamin C/Ascorbate

TET1//2/3

MDS, AML

Completed (identifies an appropriate dose of the drug combination for phase II studies)

Phase I

In combination with Decitabine and Arsenic trioxide

NCT00671697³³⁶

Vitamin C/Ascorbate

TET1//2/3

TET2-mutant MDS, TET2-mutant AML

Completed (unpublished)

Phase II

In combination with Azacitidine

NCT03397173

Vitamin C/Ascorbate

TET1//2/3

TET2-mutant MDS

Completed (exhibits good safety profiles and tolerability)

Phase I/II

—

NCT03433781