NCT04198818

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patient With Advanced Tumors

Terminated Phase 1, PHASE2 Results posted Last updated 19 July 2024

What this trial tests

Phase 1, PHASE2 trial testing HH2710 in Advanced Tumors in 37 participants. Terminated before completion.

Timeline

7 January 2020

Primary endpoint
31 March 2023

31 March 2023

Quick facts

Lead sponsor	Haihe Biopharma Co., Ltd.
Phase	Phase 1, PHASE2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	37
Start date	7 January 2020
Primary completion	31 March 2023
Estimated completion	31 March 2023
Sites	3 locations across China, United States

Drugs / interventions tested

• HH2710 — full drug profile →

Conditions studied

• Advanced Tumors — all drugs for Advanced Tumors →
• Melanoma — all drugs for Melanoma →
• Non-Small-Cell Lung Cancer — all drugs for Non-Small-Cell Lung Cancer →
• Erdheim-Chester Disease — all drugs for Erdheim-Chester Disease →

Sponsor

Haihe Biopharma Co., Ltd. — full company profile →

Who can join

18 and older, any sex, with Advanced Tumors or Melanoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

MTD (Maximum Tolerated Dose) Primary · Up to 1 cycle (21 days)

MTD estimation: After the escalation is completed, select the MTD based on the isotonic regression. Specifically, select the MTD for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.

Group	Value	95% CI
All Participants	NA

Number of Participants Who Experienced DLT (Dose Limiting Toxicities) Primary · Up to 1 cycle (21 days)

DLT is defined as: any toxicity meeting the specified criteria and considered at least possibly related to HH2710 (i.e., any toxicity for which a clear alternative etiology such as disease progression has not been identified) should be considered a DLT per National Cancer Institute Common Terminology Criteria for Adverse events (NCI-CTCAE V5.0) standard, which met any of the following, NCI-CTCAE V5.0 will be used for all grading, and compliance of 80% (i.e. 17 of 21 days) in Cycle 1 is required for a patient to be included in the DLT evaluation. For the purpose of dose-escalation decisions, DL

Group	Value	95% CI
HH2710 25mg BID	0
HH2710 50mg BID	0
HH2710 100mg BID	0
HH2710 200mg BID	0
HH2710 300mg QD	0
HH2710 400mg QD	0
HH2710 600mg QD	0
HH2710 800mg QD	2

Tumor Objective Response Rate (ORR) Primary · Up to 1 cycle (21 days)

ORR=CR+PR. ORR was defined as the percentage of patients who had at least one confirmed response of CR or PR defined by RECIST version 1.1 prior to any evidence of progression, and was calculated and summarized by the treatment group, along with the 95% confidence interval (CI) calculated by the Clopper-Pearson method.

Group	Value	95% CI
HH2710 25mg BID	0	0 – 70.8
HH2710 50mg BID	0	0 – 70.8
HH2710 100mg BID	0	0 – 60.2
HH2710 200mg BID	0	0 – 41.0
HH2710 300mg QD	0	0 – 60.2
HH2710 400mg QD	0	0 – 60.2
HH2710 600mg QD	0	0 – 36.9
HH2710 800mg QD	0	0 – 60.2

Pharmacokinetic Measures - Peak Time (Tmax) Secondary · C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.

Measure of time to reach maximum (peak) plasma concentration(s)

Single Dose Administration

Group	Value	95% CI
HH2710 25mg BID	1	0.5 – 3
HH2710 50mg BID	2	1 – 2
HH2710 100mg BID	2.5	1 – 24
HH2710 200mg BID	2	1 – 24
HH2710 300mg QD	4	1 – 24
HH2710 400mg QD	2.5	2 – 3
HH2710 600mg QD	2	0.5 – 4
HH2710 800mg QD	7	3 – 8

Multiple-dose Administration

Group	Value	95% CI
HH2710 25mg BID	1	1 – 24
HH2710 50mg BID	1.5	1 – 2
HH2710 100mg BID	2	2 – 2
HH2710 200mg BID	3	2 – 3
HH2710 300mg QD	8	1 – 24
HH2710 400mg QD	6	2 – 8
HH2710 600mg QD	4	2 – 24

Pharmacokinetic Measures - Peak Plasma Concentration (Cmax) Secondary · C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.

Measure the maximum (peak) plasma concentration(s)

Single Dose Administration

Group	Value	95% CI
HH2710 25mg BID	281	± 37.1
HH2710 50mg BID	382	± 59.7
HH2710 100mg BID	826	± 66.1
HH2710 200mg BID	1440	± 70.2
HH2710 300mg QD	1389	± 131.1
HH2710 400mg QD	1926	± 82.5
HH2710 600mg QD	3462	± 45.6
HH2710 800mg QD	5313	± 88.0

Multiple-dose Administration

Group	Value	95% CI
HH2710 25mg BID	920	± 77.2
HH2710 50mg BID	1038	± 22.0
HH2710 100mg BID	2115	± 17.1
HH2710 200mg BID	2130	± 61.2
HH2710 300mg QD	1112	± 42.6
HH2710 400mg QD	1933	± 83.3
HH2710 600mg QD	6519	± 6519

Pharmacokinetic Measures - Plasma Concentration Timecurve From Time 0 to Time (t) (AUC0-t) Secondary · C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.

Measure the variation of concentration in blood plasma as a function of time

Single Dose Administration

Group	Value	95% CI
HH2710 25mg BID	2858	± 58.4
HH2710 50mg BID	3139	± 52.6
HH2710 100mg BID	7683	± 61.0
HH2710 200mg BID	16027	± 67.0
HH2710 300mg QD	11369	± 87.9
HH2710 400mg QD	20546	± 66.7
HH2710 600mg QD	37032	± 25.8
HH2710 800mg QD	79134	± 64.0

Multiple-dose Administration

Group	Value	95% CI
HH2710 25mg BID	16619	± 108.2
HH2710 50mg BID	13738	± NA
HH2710 100mg BID	34387	± 23.5
HH2710 200mg BID	29611	± 91.5
HH2710 300mg QD	17572	± 39.6
HH2710 400mg QD	28267	± 69.8
HH2710 600mg QD	64857	± 95.3

Pharmacokinetic Measures -Plasma Elimination Half-life (t1/2) Secondary · Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available)

Terminal half-life, defined as 0.693 (ln2) divided by Lambda z. And t1/2，Lambda z (λz), Vz/F, are only applicable for single dose administration.

Group	Value	95% CI
HH2710 25mg BID	16	± 12
HH2710 50mg BID	15.6	± 12.6
HH2710 100mg BID	12.2	± 6.5
HH2710 200mg BID	37.9	± 16.7
HH2710 300mg QD	8.8	± 1.1
HH2710 400mg QD	12.4	± 3.5
HH2710 600mg QD	8.9	± 2.9
HH2710 800mg QD	20.9	± 1.1

Pharmacokinetic Measures - Plasma Clearance Rate Constant, Lambda z (λz) Secondary · Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available)

Terminal phase rate constant, determined by linear regression of at least 3 points on the terminal phase of the log-linear plasma concentration-time curve. The correlation coefficient (r2) for the goodness of the fit of the regression line through the data points has to be 0.85 or higher for the value to be considered reliable. If the WinNonlin data points are not on the linear portion of the terminal slope, the data points will be selected manually prior to calculation of Lambda\_z. And t1/2，Lambda z (λz), Vz/F，these 3 PK parameters are only applicable for single dose administration.

Group	Value	95% CI
HH2710 25mg BID	6.1	± 3.7
HH2710 50mg BID	6.4	± 3.7
HH2710 100mg BID	3	± 2.6
HH2710 200mg BID	2.2	± 1.2
HH2710 300mg QD	8	± 1
HH2710 400mg QD	6	± 1.6
HH2710 600mg QD	5.4	± 3.7
HH2710 800mg QD	3.3	± 0.2

Pharmacokinetic Measures - Apparent Clearance (CL/F) Secondary · C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h ;C1D2, pre-dose and 24h; C1D7,C1D10, pre-dose.C1D15 at pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h, C1D16 pre-dose and 24h,C1D22 pre-dose,and C2D1,C3D1,C5D1,C7D1,C9D1 pre-dose.

Measure apparent total clearance(s) from plasma after oral

Single Dose Administration

Group	Value	95% CI
HH2710 25mg BID	8.2	± 5.6
HH2710 50mg BID	14.7	± 9.5
HH2710 100mg BID	9.3	± 4.7
HH2710 200mg BID	13.6	± 19.3
HH2710 300mg QD	26.5	± 21.2
HH2710 400mg QD	23.3	± 21.6
HH2710 600mg QD	14.4	± 5
HH2710 800mg QD	4.1	± 1.6

Multiple-dose Administration

Group	Value	95% CI
HH2710 25mg BID	5.1	± 3.2
HH2710 50mg BID	5.9	± 0.1
HH2710 100mg BID	5.5	± 1.2
HH2710 200mg BID	21.3	± 18.8
HH2710 300mg QD	18.9	± 7
HH2710 400mg QD	18.5	± 8.7
HH2710 600mg QD	6.8	± 2.8

Pharmacokinetic Measures - Apparent Volume of Distribution (Vz/F) Secondary · Single dose, C1D1,pre-dose,15min,30min,1h,2h,3h,4h,6h,8h,12h(if available),C1D2, pre-dose(if available)

The apparent volume of distribution during terminal phase (associated with λz)(volume). And t1/2，Lambda z (λz), Vz/F，these 3 PK parameters are only applicable for single dose administration.

Group	Value	95% CI
HH2710 25mg BID	126.5	± 30.4
HH2710 50mg BID	218.9	± 32.3
HH2710 100mg BID	151.9	± 104.7
HH2710 200mg BID	454	± 505
HH2710 300mg QD	353	± 311.6
HH2710 400mg QD	385	± 328
HH2710 600mg QD	184	± 82
HH2710 800mg QD	122	± 42

Adverse events — posted to ClinicalTrials.gov

Time frame: up to 30 days after the last dose administration for each participate, and an average of 24 weeks.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

HH2710 25mg BID

Serious: 1/3 (33%)

Deaths: 2/3

HH2710 50mg BID

Serious: 2/3 (67%)

Deaths: 1/3

HH2710 100mg BID

Serious: 1/4 (25%)

Deaths: 1/4

HH2710 200mg BID

Serious: 3/7 (43%)

Deaths: 4/7

HH2710 300mg QD

Serious: 3/4 (75%)

Deaths: 1/4

HH2710 400mg QD

Serious: 1/4 (25%)

Deaths: 2/4

HH2710 600mg QD

Serious: 5/8 (63%)

Deaths: 6/8

HH2710 800mg QD

Serious: 1/4 (25%)

Deaths: 2/4

Serious adverse events (25 terms)

Reaction	System	HH2710 25mg BID	HH2710 50mg BID	HH2710 100mg BID	HH2710 200mg BID	HH2710 300mg QD	HH2710 400mg QD	HH2710 600mg QD	HH2710 800mg QD
Intestinal obstruction	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Small intestinal obstruction	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—
Duodenal ulcer	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Escherichia bacteraemia	Infections and infestations	—	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—
Urinary tract infection bacterial	Renal and urinary disorders	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Central serous chorioretinopathy	Eye disorders	—	—	—	—	—	—	—	—
Cystoid macular oedema	Eye disorders	—	—	—	—	—	—	—	—
Macular oedema	Eye disorders	—	—	—	—	—	—	—	—
Retinal vein occlusion	Eye disorders	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—	—	—	—	—	—	—
Hyperbilirubinaemia	Hepatobiliary disorders	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Supraventricular tachycardia	Cardiac disorders	—	—	—	—	—	—	—	—
Malignant pleural effusion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—
Dermatitis contact	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Haematoma	Vascular disorders	—	—	—	—	—	—	—	—

Other adverse events (20 terms — click to expand)

Reaction	System	HH2710 25mg BID	HH2710 50mg BID	HH2710 100mg BID	HH2710 200mg BID	HH2710 300mg QD	HH2710 400mg QD	HH2710 600mg QD	HH2710 800mg QD
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—
Bilirubin conjugated increased	Investigations	—	—	—	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—

Most-reported serious reactions: Intestinal obstruction, Small intestinal obstruction, Pyrexia, Duodenal ulcer, Nausea, Vomiting, Escherichia bacteraemia, Pneumonia.

Data from ClinicalTrials.gov NCT04198818 adverse events section.

Sponsor's own description

This is a First-in-Human, Open Label, Phase I/II Study to Evaluate the Safety, Tolerability and Pharmacokinetics of HH2710 in Patients with Advanced Tumors, composed of a Phase I dose escalation and dose expansion stage and a Phase II dose extension stage.

Publications & conference data

4 peer-reviewed publications reference this trial (live from Europe PMC):

1. Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy.
   Pan X, Pei J, Wang A, Shuai W, et al · · 2022 · cited 49× · PMID 35646548 · DOI 10.1016/j.apsb.2021.12.022
2. CDK4/6 and MAPK-Crosstalk as Opportunity for Cancer Treatment.
   Scheiblecker L, Kollmann K, Sexl V. · · 2020 · cited 34× · PMID 33255177 · DOI 10.3390/ph13120418
3. Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications.
   Vanni I, Tanda ET, Dalmasso B, Pastorino L, et al · · 2020 · cited 29× · PMID 32850962 · DOI 10.3389/fmolb.2020.00172
4. The future of targeted kinase inhibitors in melanoma.
   Caksa S, Baqai U, Aplin AE. · · 2022 · cited 25× · PMID 35513054 · DOI 10.1016/j.pharmthera.2022.108200