Clinical trial NCT03710915: A Study of HG146 Capsule in Chinese Subjects with Relapsed and Refractory Multiple Myeloma
Official title: A Phase I Study of Single-centre, Open-label Clinical Trial to Evaluate HG146 Capsule in the Treatment of Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Multiple Myeloma
Relapsed and Refractory Multiple Myeloma
Keywords: HDAC inhibitor
Dose escalation
HG146
Lead sponsor: HitGen Inc.
Sponsor class: INDUSTRY
First posted: 2018-10-18
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Drug: HG146 capsule HG146 capsule is a histone deacetylase inhibitor (HDAC inhibitor) for the treatment of multiple myeloma.

Other Name: HG280146, HG0146, HG280146, HG280146-P1
Primary purpose: TREATMENT

Brief summary: This study is designed to evaluate the tolerability and safety of HG146 capsule in patients with multiple myeloma.

Detailed description: This study is mainly designed to evaluate the tolerability and safety of HG146 capsule in patients with multiple myeloma. Secondly, to get pharmacokinetic data and preliminary efficacy of HG146 capsule in human.

This study adopts the traditional design of "3 + 3" dose escalation. The starting dose is 5 mg and subsequent dose group is respectively for 10, 15 and 20 mg. For each dosing group, subjects are administered orally HG146 every other day for two weeks, followed by one week of rest with 21-day as one treatment cycle. Patients will be treated for 4 cycles or disease progression or unacceptable toxicities, whichever comes first.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of multiple myeloma requiring systemic therapy (International Myeloma Working Group \[IMWG\]) and 2 cycles of treatment including proteasome inhibitors and/or immunomodulators.
* Serum M protein≥ 10.0g / L, or urine M protein ≥ 200mg / 24h.
* Not suitable for autologous bone marrow transplantation or refuse autologous bone marrow transplantation or relapse after autologous bone marrow transplantation.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or 2.
* Expected survival of ≥3 months.
* Hemoglobin ≥ 80 g/L, Platelet≥75×10\^9/L, Absolute Neutrophil Count≧1.0×109/L (1000 cells/mm3), Prothrombin time(PT) and activated partial thromboplastin time ≤ 2 x Upper Limit of Normal (ULN).
* Bilirubin in serum\<1.5\*ULN (2.0mg/dL/20mg/L/34.2μmol/L); glutamic-pyruvic transaminase (ALT) and/or Aspartate Aminotransferase (AST)≤3\*ULN (upper limit of normal).
* Normal electrocardiogram, echocardiography and myocardial enzyme spectrumCalibration of blood calcium concentration≤ULN.
* Men and women, Non-pregnant women who did not consider giving birth during the trial or five years after the end of the trial.
* The patient is able to swallow the capsule.
* Patients must provide written consent.

Exclusion Criteria:

* Severe allergies to the study drug or any of its excipients.
* The possibility of gene toxicity, mutagenesis and teratogenicity.
* Men and women who did not have sperm or egg cells stored in vitro before the trial and who planned to have children again within five years.
* Pregnant or lactating women.
* Perform autologous bone marrow transplantation 3 months before admission.
* Receive allogeneic bone marrow transplantation.
* Use HDAC inhibitors before.
* Two weeks prior to admission, received radiotherapy or bone marrow suppressive chemotherapy or biological treatment.
* Patients with history of other malignant tumors, except the tumor is in remission and has not been treated for at least 5 years.
* Patients with dysphagia or oral absorption disorder.
* The investigators determine the conditions not suitable for the study.

Primary outcomes:
measure: Maximum tolerated dose of HG146
timeFrame: Up to 3 months
Secondary outcomes:
measure: Peak Plasma Concentration (Cmax)
timeFrame: In cycle 1 (each cycle is 21 days)
measure: Area under the plasma concentration versus time curve (AUC)
timeFrame: In the middle of cycle 1 (each cycle is 21 days)
measure: Time of Peak Concentration (Tmax)
timeFrame: In the middle of cycle 1 (each cycle is 21 days)
measure: Half life (T1/2)
timeFrame: In the middle of cycle 1 (each cycle is 21 days)
measure: Incidence of adverse events related to treatments
timeFrame: Up to 21 days after last dose
measure: Incidence of laboratory abnormalities related to treatments
timeFrame: Up to 1 month after last dose
Other outcomes:
Locations:
city: Chengdu
country: China
facility: HitGen Inc
state: Sichuan
Study officials:
affiliation: The West China Hospital of Sichuan University
name: Ting Liu, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huang B, Lu J, Wang X, Xiao Y, Zhao Y, Huang H, Liu J, Chen M, Gu J, Yuan S, Zheng D, Li Y, Huang X, Li J. Prognostic value of lactate dehydrogenase in Chinese patients with newly diagnosed transplant eligible multiple myeloma. Leuk Lymphoma. 2017 Jul;58(7):1740-1742. doi: 10.1080/10428194.2016.1252975. Epub 2016 Nov 23. No abstract available.
citation: Lu J, Lu J, Chen W, Huo Y, Huang X, Hou J; Chinese Medical Doctor Association Hematology Branch. Clinical features and treatment outcome in newly diagnosed Chinese patients with multiple myeloma: results of a multicenter analysis. Blood Cancer J. 2014 Aug 15;4(8):e239. doi: 10.1038/bcj.2014.55.
citation: Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 2014 Oct 26.
citation: Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. doi: 10.1002/1097-0142(197509)36:33.0.co;2-u.
citation: Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. doi: 10.1200/JCO.2015.61.2267. Epub 2015 Aug 3.
citation: Lu J, Lee JH, Huang SY, Qiu L, Lee JJ, Liu T, Yoon SS, Kim K, Shen ZX, Eom HS, Chen WM, Min CK, Kim HJ, Lee JO, Kwak JY, Yiu W, Chen G, Ervin-Haynes A, Hulin C, Facon T. Continuous treatment with lenalidomide and low-dose dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial. Br J Haematol. 2017 Mar;176(5):743-749. doi: 10.1111/bjh.14465. Epub 2017 Jan 20.