A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of DXP-106 as Monotherapy or in Combination With Standard of Care Chemotherapy in Patients With Advanced Solid Tumors.
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Enrollment
- 54
- Locations
- 5
- Primary Endpoint
- Dose-limiting toxicities (DLTs) within the first cycle of administraton of DXP-106
Study Overview
Brief Summary
The goal of this clinical trial is to evaluate the safety and tolerability of DXP-106 in Chinese patients with advanced solid tumors. The main questions it aims to answer are:
For Part I:
- The safety and tolerability of DXP-106 monotherapy in patients with advanced solid tumors;
- The dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D);
- The pharmacokinetics (PK) profile, the immunogenicity of DXP-106 following administration in patients with advanced solid tumors;
- The preliminary efficacy of DXP-106 in patients with advanced solid tumors;
- The pharmacodynamic (PD) profiles of DXP-106 following administration in patients with advanced solid tumors as exploratory objective;
For Part2:
- The safety and tolerability of DXP-106 in combination with standard of care chemotherapy in patients with advanced solid tumors;
- The recommended dose of DXP-106 in combination with standard of care chemotherapy and/or potential responsive tumor types;
- The efficacy of DXP-106 in combination with standard of care chemotherapy in patients with advanced solid tumors;
- The PK profile and immunogenicity of DXP-106 in combination with standard of care chemotherapy in patients with advanced solid tumors;
- The PD profiles of DXP-106 in combination with standard of care chemotherapy in patients with advanced solid tumors.
The dose escalation is designed with five cohorts, including Cohort 1 (1.0 mg/kg), Cohort 2 (2.0 mg/kg), Cohort 3 (4.0 mg/kg), Cohort 4 (6.0 mg/kg), and Cohort 5 (8.0 mg/kg) in part 1. Each treatment cycle consists of 4 weeks, with administration once weekly (QW) in the first cycle and once every two weeks (Q2W) in subsequent cycles. Treatment will continue until disease progression, unacceptable toxicity, death, loss to follow-up, withdrawal of consent, or discontinuation due to other reasons. Based on the continuously obtained data from Part 1 monotherapy dose escalation, the Part 2 combination therapy exploration will be scheduled to commence. The combination therapy dose-escalation is planned to include three dose levels, tentatively designated as Dose Level 1 (DL1), DL2, and DL3 in PDAC patients. Dose escalation will follow the "traditional 3+3" rule, proceeding sequentially from DL1 to DL3. Safety Review Committee (SRC) will determine whether to proceed with escalation to higher doses based on available data, including but not limited to safety, tolerability, PK/PD, and preliminary efficacy. The SRC will discuss and make appropriate decisions when any other unanticipated circumstances occur during the clinical trial.
Detailed Description
To accurately assess DLT, DLT-evaluable subjects are defined as one who meets any of the following criteria during the DLT evaluation period:
- The patient experiences a DLT at any time after DXP-106 infusion during the DLT observation period.
- The patient completes at least 75% of the planned total dose of DXP-106 infusion during the DLT evaluation period and have fulfilled the safety evaluation requirements during the DLT observation period.
For Part 1 (monotherapy dose escalation) and Part 2 (combination therapy dose escalation) of this study, patients who discontinue prior to completion of the DLT evaluation period in the first cycle after the first dose for reasons other than DLT, or who do not meet any of the above criteria, will be considered non-evaluable for DLT.
Subjects who are not evaluable for DLT due to non-DLT reasons will be replaced, leading to an increase in the actual sample size.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants who fully understand the trial objectives, nature, procedures, and potential adverse reactions, and who voluntarily agree to participate in the study and provide signed informed consent.
- •Patients aged 18 to 80 years (inclusive, based on the date of signing the informed consent form), both male and female.
- •Measurable disease as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST criteria within 4 weeks prior to screening.
- •Study Population
- •Part 1: Patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors who are ineligible for surgery or curative radiotherapy and have experienced disease progression after standard treatment or are intolerant to such therapy. Target tumor types include but are not limited to colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), head and neck squamous cell carcinoma, lung cancer (LC), Ewing sarcoma (ES), and triple-negative breast cancer (TNBC).
- •Part 2: If the participant received adjuvant/neoadjuvant therapy before or after completing prior curative treatment, and the participant's disease has recurred, the interval between the end of adjuvant/neoadjuvant therapy and the first dose in this study must exceed 6 months.
- •LC patients: Patients with locally advanced/metastatic lung cancer confirmed by histology or cytology, who relapsed after first-line treatment and must meet the criteria for receiving platinum-based chemotherapy as first-line or second-line standard treatment;
- •PDAC Patients: Patients with newly diagnosed histologically or cytologically confirmed, unresectable or radiotherapeutically ineligible locally advanced or metastatic PDAC, who have not received previous treatment and are eligible for standard of care chemotherapy regimens.
- •ES patients: Patients with pathologically confirmed unresectable or locally advanced or metastatic Ewing's sarcoma that has failed standard treatment, and a detailed pathological report must be provided. Patients have received at least 1 but no more than 2 lines of systemic therapy previously, and must be eligible for standard chemotherapy regimens.
- •TNBC patients (for patients with bilateral breast cancer, both sides must be TNBC): Patients with histologically or cytologically confirmed, inoperable locally advanced or metastatic breast cancer, with ER, PR, and HER-2 all negative. The definition of ER and PR negativity is: IHC ER < 1%, IHC PR < 1%. The definition of HER-2 negativity is: IHC HER-2 (-) or (1+); for those with HER-2 (2+), FISH testing must be performed and the result must be negative. Patients must be eligible for standard chemotherapy regimens;
- •Eastern Cooperative Oncology Group (ECOG) performance score of 0 to
- •Life expectancy > 3 months.
- •Adequate organ function meeting the following criteria:
- •Hematology (without transfusion, hematopoietic growth factors, or medication to correct blood cell counts within 14 days prior to first dose): absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 75 × 109/L (part1) or platelet count ≥ 100 × 109/L (part2), hemoglobin ≥ 9.0 g/dL.
- •Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × upper limit of normal (ULN) (for patients not receiving anticoagulant therapy); patients on oral anticoagulants with an INR between 2 and 3 were eligible.
- •Hepatic function: Total bilirubin (TBIL) ≤ 1.5 × ULN ); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; ALT and AST≤ 5.0 × ULN for patients with primary hepatocellular carcinoma (HCC) or hepatic metastases.
- •Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance > 50 mL/min (calculated using the Cockcroft-Gault formula).
- •Both female and male patients of reproductive potential must have agreed to use reliable contraceptive methods during the trial and for 6 months after the last dose.
Exclusion Criteria
- •Participants with a history of hypersensitivity, particularly those allergic to the investigational drug or its excipients, or those who have previously experienced severe allergic reactions to macromolecular protein preparations/monoclonal antibodies.
- •Participants who have received live/live attenuated vaccines, etanercept or other TNF-α inhibitors, or any other investigational drug during or prior to participation in this study (within 4 weeks before the first dose of the investigational drug or within 5 half-life of the investigational drug, whichever is longer).
- •In Part 2, LC patients have received other anti-tumor drug treatments in addition to first-line treatment medications; patients with gene mutations that can be used as targets for targeted therapy (including but not limited to EGFR, ALK, ROS, KRAS) (excluding patients who have progressed on standard targeted therapy and whose next-line standard treatment is a platinum-based dual-drug regimen).
- •The toxicity from previous treatments has not alleviated to the level specified in the inclusion/exclusion criteria or to NCI CTCAE ≤ Grade 1 (except for alopecia, pigmentation, Grade 2 peripheral neuropathy, adrenal insufficiency, and other toxicities deemed by the investigator to pose no safety risk to the participant).
- •Presence of other active malignancies besides the primary tumor within the past 2 years, with the following exceptions: participants cured with curative-intent therapy and without evidence of recurrence, such as basal cell carcinoma, cutaneous squamous cell carcinoma, superficial bladder carcinoma, papillary thyroid carcinoma, carcinoma in situ of the cervix, or breast carcinoma in situ.
- •History of active autoimmune disease requiring treatment with systemic immunosuppressive agents, or participants requiring systemic immune-related therapy due to immunocompromise from any cause, including but not limited to autoimmune conditions such as systemic lupus erythematosus and active psoriasis.
- •Active infection requiring intravenous treatment or unexplained body temperature >38.5°C during the screening period.
- •Major surgery within 4 weeks prior to the first dose of the investigational drug.
- •Prior cell therapy within 3 months before the first dose of the investigational drug.
- •Immunocompromised individuals requiring systemic treatment.
- •Participants with significant cardiovascular disease, defined as any of the following:
- •Congestive heart failure with New York Heart Association (NYHA) Class ≥ 3; left ventricular ejection fraction (LVEF) < 50%;
- •History of acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months prior to enrollment;
- •Malignant arrhythmias requiring pharmacotherapy, second- or third-degree atrioventricular block; congenital long QT syndrome, or prolongation of QT/QTc interval on screening electrocardiogram (QTcF: >450 ms for males and >470 ms for females, calculated using Fridericia's method. If QTc is abnormal, up to 3 consecutive measurements may be obtained at intervals ≤5 minutes and the average value used);
- •Uncontrolled hypertension despite pharmacologic management (hypertension inadequately controlled with medications, with systolic blood pressure ≥150 mmHg and diastolic blood pressure ≥100 mmHg);
- •Other cardiac abnormalities judged by the investigator to be clinically significant and likely to compromise study safety.
- •Presence of severe pulmonary disease at screening, such as pulmonary embolism or interstitial lung disease, with severely impaired pulmonary function as judged by the investigator.
- •Newly diagnosed brain metastases or brain metastases with central nervous system symptoms, or other evidence indicating uncontrolled metastases who are considered ineligible per investigator assessment. Participants with leptomeningeal metastases are not recommended for enrollment. Participants with brain metastases may be enrolled if they are clinically stable as assessed by the investigator following treatment and do not require steroid therapy for at least 28 days prior to the first study dose.
- •Seropositive for syphilis antibody; positive HIV test; presence of active hepatitis B [Active hepatitis B (HBV) is defined as positive HBsAg or positive HBcAb with HBV DNA greater than the upper limit of the site reference range (i.e., above the lower limit of detection). If HBV DNA is positive (above the lower limit of detection), participants may receive anti-HBV antiviral therapy and may be rescreened. Participants may be enrolled if HBV DNA falls below the lower limit of detection after treatment.] or active hepatitis C [Active hepatitis C is defined as positive HCV RNA (HCV RNA level above the lower limit of detection)].
- •History of allogeneic tissue/solid organ transplantation requiring immunosuppressive therapy.
- •Patients who experienced immune-related toxicity during prior antitumor immunotherapy and permanently discontinued treatment as a result.
- •Severe hereditary or acquired bleeding tendency or coagulation disorder.
- •Inability to undergo venipuncture and/or tolerate venous access.
- •Pregnant or lactating women.
- •Before the first administration of the study drug, the washout period for previous systemic anti-tumor treatments is insufficient, including:
- •Chemotherapy < 3 weeks, except for oral fluorouracil (such as tegafur and capecitabine), which requires 2 weeks or within 5 half-lives before the first administration, whichever is shorter;
- •Small molecule targeted therapy < 2 weeks or 5 half-lives, whichever is shorter;
- •Antibody therapy (including ADC) or biological therapy < 3 weeks;
- •Traditional Chinese medicines with anti-tumor indications or non-specific immunomodulators (such as thymosin, interferon, interleukin, and traditional Chinese medicines with clear immunomodulatory indications, etc.) < 2 weeks.
- •Definitive radiotherapy < 4 weeks, limited-field local palliative radiotherapy < 2 weeks.
- •Endocrine anti-tumor therapy or small-molecule immunotherapy < 2 weeks or 5 half-lives, whichever is shorter.
- •Any other condition considered by the investigator as potentially affecting the participant's ability to provide informed consent or comply with the trial protocol, or that may influence the trial results or participant safety.
Arms & Interventions
DXP-106
The study includes Part 1 (monotherapy dose escalation) and Part 2 (combination therapy dose escalation). In Part 1, five cohorts are planned. The first cohort is expected to enroll approximately 1 to 6 patients, and the remaining cohorts are planned to enroll approximately 3 to 6 patients each. In Part 2, the PDAC, LC, TNBC, EWS tumor types are tentatively selected, with approximately 3-6 patients planned for enrollment. Backfilling may be considered at dose levels in some indications deemed safe and demonstrating efficacy signals, with approximately 6-12 subjects to be enrolled via backfilling. A total of approximately 24 subjects are expected to be enrolled in Part 2. Overall, the study plans to enroll approximately 40 to 54 subjects.
Intervention: DXP-106 (Drug)
Outcomes
Primary Outcomes
Dose-limiting toxicities (DLTs) within the first cycle of administraton of DXP-106
Time Frame: From the first administration of DXP-106 on Cycle1Day1, including priming dose if any to the end of cycle1, assessed up to 4 weeks.
The severity of adverse events will be assessed and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 6.0 (United States). A DLT is defined as any of the following adverse events occurring during the first cycle (starting from the first intravenous infusion of DXP-106, including priming dose if any) in either Part 1 (monotherapy dose escalation) or Part 2 (combination therapy dose escalation), including but not limited to: hematologic Toxicity; hepatic toxicity; other Grade ≥3 non-Hematologic toxicity; delays in subsequent treatment cycles exceeding 14 days due to persistent toxicity; any death clearly unrelated to the underlying disease or external causes.
Adverse events(AE) and serious adverse events(SAE)
Time Frame: From first administration of DXP-106 to safety follow up completion, assessed up to 13 months.
It will be assessed by the frequency, severity and nature of AEs, serious adverse event (SAE), changes in vital signs, physical examination, 12-lead ECG, infusion-related reactions and laboratory tests (haematology, serum chemistry, and urine), etc. The severity of AEs will be graded by the NCI CTCAE version 6.0 and the AE terms will be coded by the current version of the Medical Dictionary for Regulatory Activities (MedDRA).
Dose-limiting toxicities (DLTs) within the first cycle of administraton of DXP-106
Time Frame: From the first administration of DXP-106 on Cycle1Day1, including priming dose if any to the end of cycle1, assessed 4 weeks following C1D1 administration.
The severity of adverse events will be assessed and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 6.0 (United States). A DLT is defined as any of the following adverse events occurring during the first cycle (starting from the first intravenous infusion of DXP-106, including priming dose if any) in either Part 1 (monotherapy dose escalation) or Part 2 (combination therapy dose escalation), including but not limited to: hematologic Toxicity; hepatic toxicity; other Grade ≥3 non-Hematologic toxicity; delays in subsequent treatment cycles exceeding 14 days due to persistent toxicity; any death clearly unrelated to the underlying disease or external causes.
Secondary Outcomes
- Exposure levels of DXP-106 when administered in participants (Pharmacokinetics)(From the first administration of DXP-106 to the end of treatment, assessed up to 12 months.)
- Anti-drug antibodies (ADAs) against DXP-106 (Immunogenicity)(From the first administration of DXP-106 to the end of treatment, assessed up to 12 months.)
- Objective response rate (ORR)(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Disease Control Rate (DCR)(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Overall Survival (OS)(survival follow-up will be conducted once every 12 weeks (±4 weeks) after end of treatment visit until death, withdrawal of informed consent, loss to follow-up, or the data cutoff date, whichever comes first. assessed up to 12 months.)
- Progression-Free Survival (PFS)(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Duration of Response (DoR)(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Exposure levels of DXP-106 when administered in participants (Pharmacokinetics)(From the first administration of DXP-106, including priming dose if any, to the end of treatment, assessed up to 12 months.)
- Anti-drug antibodies (ADAs) against DXP-106 (Immunogenicity)(From the first administration of DXP-106, including priming dose if any, to the end of treatment, assessed up to 12 months.)
- Objective response rate (ORR and iORR)(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Disease Control Rate (DCR and iDCR)(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Progression-Free Survival (PFS) and iPFS(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)
- Duration of Response (DoR) and iDOR(From date of first administration until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 12 months.)