Clinical trial NCT03616574: First-in-human Study of CA102N Monotherapy and CA102N Combined With Trifluridine/Tipiracil (LONSURF) in Subjects With Advanced Solid Tumors
Official title: Phase 1,Two-part (Dose Escalation, Dose Expansion), Multicenter,Non-randomized,Open-label, Multiple Dose, First-in-human Study of CA102N Monotherapy and of CA102N Combined With Trifluridine/Tipiracil (LONSURF) in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced or Metastatic Solid Tumors
Advanced or Metastatic Colorectal Cancer (mCRC)
Lead sponsor: Holy Stone Healthcare Co., Ltd
Sponsor class: INDUSTRY
First posted: 2018-08-06
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 (dose escalation) of the study will use a conventional 3+3 design (3 subjects per dose cohort, with the potential to add an additional 3 subjects if dose limiting toxicity \[DLT\] is observed at the same dose level at which the toxicity occurred). Enrollment will occur in 2 groups, CA102N monotherapy (Group A) and CA102N combination therapy (Group B).

Subjects will be enrolled in Group A first. Once enrollment in Group A has been completed, subsequent subjects will be enrolled in Group B.

In Part 2 of the study, the safety and tolerability of the preliminary RP2D of CA102N combined with trifluridine/tipiracil (LONSURF) will be further evaluated in up to 12 additional subjects with relapsed or refractory locally advanced or metastatic colorectal cancer who have previously received oxaliplatin and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
Primary purpose: TREATMENT

Brief summary: Study HS-CA102N-101 is a phase 1, two part (dose escalation, dose expansion), multicenter, non-randomized, open-label, multiple dose, first-in-human study of CA102N monotherapy and of CA102N combined with trifluridine/tipiracil (LONSURF) in subjects with advanced solid tumors.

CA102N will be evaluated in subjects with locally advanced or metastatic solid tumours for which no effective therapy is available in Part 1 (dose escalation) and in subjects with relapsed or refractory locally advanced or metastatic colorectal cancer (mCRC) after prior oxaliplatin and irinotecan-based chemotherapy in Part 2 (dose expansion).

Detailed description: Study HS-CA102N-101 is a phase 1, two part (dose escalation, dose expansion), multicenter, non-randomized, open-label, multiple dose, first-in-human study of CA102N monotherapy and of CA102N combined with trifluridine/tipiracil (LONSURF) in subjects with advanced solid tumors.

Part 1 (dose escalation) will determine the safety and tolerability of three dose levels of CA102N as monotherapy and the safety, tolerability and preliminary recommended phase 2 dose (RP2D) of CA102N in combination with trifluridine/tipiracil (LONSURF) in patients with locally advanced or metastatic solid tumors.

Part 2 (dose expansion) will further investigate the safety and tolerability of the combination of CA102N and trifluridine/tipiracil (LONSURF) at the preliminary RP2D in patients with locally advanced or metastatic colorectal cancer that has relapsed after or is refractory to oxaliplatin and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and if RAS wild-type metastatic colorectal cancer, an anti-epidermal growth factor receptor (EGFR) therapy..

Preliminary efficacy will be evaluated in Parts 1 and 2 of the study as an exploratory endpoint.

Eligibility criteria: Inclusion Criteria:

* Subjects enrolled in Part 1 must have histologically documented locally advanced or metastatic solid tumor for which there is no effective therapy available.
* Subjects enrolled in Part 2 must have histologically documented locally advanced or metastatic colorectal cancer that has relapsed after or is refractory to oxaliplatin and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
* Age ≥18 years (US) or ≥20 years (Taiwan).
* ECOG performance status 0-1.
* Measurable or non-measurable disease based on RECIST version 1.1. Subjects enrolled in Part 2 must have at least one measurable lesion.
* Adequate organ function within 14 days before 1st dose of study drug, defined as:

  1. Platelet count ≥ 100,000/mm3.
  2. Hemoglobin ≥ 9.0 g/dL.
  3. Absolute neutrophil count ≥ 1500/mm3 (without hematopoietic growth factor support).
  4. Creatinine ≤ 1.5 x ULN, or creatinine clearance ≥ 50 mL/min as calculated using the modified Cockcroft-Gault equation.
  5. Aspartate aminotransferase: (i) ≤3 x ULN in subjects without liver metastasis or ≤5 x ULN in subjects with liver metastasis in CA102N monotherapy treatment group; (ii) ≤3 x ULN in subjects who will be treated with CA102N combined with trifluridine/tipiracil (LONSURF).
  6. Alanine aminotransferase: (i) ≤3 x ULN in subjects without liver metastasis or ≤5 x ULN in subjects with liver metastasis in CA102N monotherapy treatment group; (ii) ≤3 x ULN in subjects who will be treated with CA102N combined with trifluridine/tipiracil (LONSURF).
  7. Total bilirubin ≤1.5 x ULN (unless documented Gilbert's Syndrome).
* Has had an adequate treatment washout period prior to 1st dose of study drug defined as:

  1. No major surgery within the past 4 weeks.
  2. No extended field radiation therapy within the prior 4 weeks.
  3. No anticancer therapy or bevacizumab within the prior 3 weeks.
  4. No investigational agent received within prior 4 weeks (or 5 times the half-life of the investigational agent, whichever is shorter).
  5. No aspirin or NSAIDs for at least 72 hours before 1st dose of study drug.
  6. No herbal supplements taken as anticancer agents within the prior 7 days.
* Able to provide written informed consent.
* Life expectancy of ≥ 3 months.
* Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective means of contraception from study entry through at least 6 months after the last dose of CA102N. Women of childbearing potential are those women who have not been permanently sterilized or are not postmenopausal.

Exclusion Criteria:

* For Part 2, active malignancies other than colorectal cancer.
* History of hypersensitivity or hepatotoxic reaction to nimesulide or to any excipient.
* Requiring therapeutic doses of anticoagulants.
* History or presence of a bleeding tendency or disorder.
* History of gastrointestinal bleed or perforation related to previous NSAID therapy.
* Presence or history of recurrent peptic ulcer or hemorrhage.
* History of cerebrovascular or other active bleeding.
* Myocardial infarction within the last 12 months, severe or unstable angina, symptomatic congestive heart failure New York Heart Association (NYHA) Class III or IV.
* History of a serious cardiac arrhythmia requiring treatment.
* Corrected QT prolongation using Fridericia formula (QTcF), of \> 450 msec for males or \> 470 msec for females based on a triplicate 12-lead ECG.
* Clinically significant lung disease (eg, interstitial pneumonia, interstitial lung disease, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) requiring continuous systemic corticosteroid treatment for 6 months before registration or who are suspected to have such diseases by imaging at Screening.
* Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks.
* Active autoimmune disease that has required systemic treatment in past 2 years.
* History of allogeneic transplantation requiring immunosuppressive therapy.
* Known positive test for hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV).
* Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.
* Pregnant or breast feeding.
* Unresolved toxicity of greater than or equal to NCI-CTCAE (version 5.0) Grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum-induced neurotoxicity).
* Concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator.

Primary outcomes:
measure: Number of subjects with treatment-related adverse events as assessed by NCI-CTCAE v5.0
timeFrame: The safety measures will be assessed and recorded throughout the trial until 30 days following treatment termination (an average of 1 year).
Secondary outcomes:
measure: Serum concentration of CA102N
timeFrame: Serum sampling timepoints: predose, 0.5,1, 2, 4, 8, 12, 24, 48, and 72 hours postdose CA102N on Days 1 and 15 at Cycle 1 (each cycle is 28 days).
Other outcomes:
measure: Tumor response according to RECIST v1.1
timeFrame: Tumor response will be evaluated after every 2 cycles of treatment (each cycle is 28 days) until the subject starts alternative anti-cancer treatment or develops progressive disease, whichever occurs first (an average of 1 year).
measure: Analysis of urinary COX-2 metabolites by LC-MS/MS
timeFrame: Urine samples will be collected at predose, 8 and 72 hours postdose CA102N on Days 1 and 15 at Cycle 1, at predose of each subsequent cycle (each cycle is 28 days), until the termination visit (an average of 1 year after Cycle 1 Day 1).
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: The University of Texas MD Anderson Cancer Center
name: Shubham Pant, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jian YS, Chen CW, Lin CA, Yu HP, Lin HY, Liao MY, Wu SH, Lin YF, Lai PS. Hyaluronic acid-nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo. Int J Nanomedicine. 2017 Mar 27;12:2315-2333. doi: 10.2147/IJN.S120847. eCollection 2017.
citation: Pant S, Dragovich T, Lieu C, Jimeno A, Kundranda M, Menter D, Tchaparian E, Chen YC, Kopetz S. Phase 1 study of the safety, pharmacokinetics, and preliminary efficacy of CA102N as monotherapy and in combination with trifluridine-tipiracil in patients with locally advanced or metastatic solid tumors. Invest New Drugs. 2023 Feb;41(1):25-34. doi: 10.1007/s10637-022-01308-5. Epub 2022 Nov 4.