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First-in-human Study of CA102N Monotherapy and of CA102N Combined With Trifluridine/Tipiracil (LONSURF) in Subjects With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03616574
Recruitment Status : Not yet recruiting
First Posted : August 6, 2018
Last Update Posted : February 25, 2019
Sponsor:
Information provided by (Responsible Party):
Holy Stone Healthcare Co., Ltd

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).


Condition or disease Intervention/treatment Phase
Advanced or Metastatic Solid Tumors Advanced or Metastatic Colorectal Cancer (mCRC) Drug: CA102N Drug: LONSURF Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation - CA102N Monotherapy
0.36, 0.54, and 0.72 mg/kg of nimesulide equivalents of CA102N on Days 1 and 15 of a 28-day cycle
Drug: CA102N
CA102N is a covalently bound conjugate of the biological polymer sodium hyaluronate (NaHA) and nimesulide (Nim).
Other Name: Nim-HA Conjugate

Experimental: Dose Escalation - CA102N plus LONSURF
0.36, 0.54, and 0.72 mg/kg of nimesulide equivalents of CA102N on Days 1 and 15 in combination with 35 mg/m2/dose of LONSURF orally twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle
Drug: CA102N
CA102N is a covalently bound conjugate of the biological polymer sodium hyaluronate (NaHA) and nimesulide (Nim).
Other Name: Nim-HA Conjugate

Drug: LONSURF
LONSURF is a cytotoxic combination treatment of 2 new drugs: trifluridine, a thymidine-based nucleoside analog, and tipiracil, an inhibitor of thymidine phosphorylase.
Other Name: Trifluridine/Tipiracil

Experimental: Dose Expansion - CA102N plus LONSURF
The preliminary RP2D of CA102N on Days 1 and 15 in combination with 35 mg/m2/dose of LONSURF orally twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle
Drug: CA102N
CA102N is a covalently bound conjugate of the biological polymer sodium hyaluronate (NaHA) and nimesulide (Nim).
Other Name: Nim-HA Conjugate

Drug: LONSURF
LONSURF is a cytotoxic combination treatment of 2 new drugs: trifluridine, a thymidine-based nucleoside analog, and tipiracil, an inhibitor of thymidine phosphorylase.
Other Name: Trifluridine/Tipiracil




Primary Outcome Measures :
  1. Number of subjects with treatment-related adverse events as assessed by NCI-CTCAE v5.0 [ Time Frame: The safety measures will be assessed and recorded throughout the trial until 30 days following treatment termination (an average of 1 year). ]
    The primary endpoint for the study is the safety and tolerability of CA102N monotherapy and CA102N combined with trifluridine/tipiracil (LONSURF) as determined according to the NCI-CTCAE version 5.0.


Secondary Outcome Measures :
  1. Serum concentration of CA102N [ Time Frame: 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). ]
    The secondary endpoint of the study is to measure serum concentration of CA102N (ng/mL).


Other Outcome Measures:
  1. Tumor response according to RECIST v1.1 [ Time Frame: 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). ]
    The exploratory endpoint of the study is to evaluate objective tumor response to CA102N monotherapy and to CA102N in combination with trifluridine/tipiracil (LONSURF) in subjects with locally advanced or metastatic solid tumors and in subjects with locally advanced or metastatic colorectal cancer. The data of tumor response will be collected and evaluated using RECIST version 1.1.

  2. Analysis of urinary COX-2 metabolites by LC-MS/MS [ Time Frame: 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). ]
    To determine the systemic alteration of COX-2 metabolites affected by CA102N by analyzing urinary COX-2 metabolites, such as PGEM, PGIM and TXBM, using LC-MS/MS.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03616574


Contacts
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Contact: Ivy Chen +886-2-87975966 ext 272 ivychen@hshc.com.tw
Contact: Jessie Wu +886-2-87975966 ext 298 jessiewu@hshc.com.tw

Sponsors and Collaborators
Holy Stone Healthcare Co., Ltd
Investigators
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Principal Investigator: Shubham Pant, MD M.D. Anderson Cancer Center

Publications:
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Responsible Party: Holy Stone Healthcare Co., Ltd
ClinicalTrials.gov Identifier: NCT03616574     History of Changes
Other Study ID Numbers: HS-CA102N-101
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: February 25, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Trifluridine
Nimesulide
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors