An Open, Multicenter, Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics/Pharmacokinetics, and Antitumor Activity of GNC-038 Quad-specific Antibody Injection in Relapsed or Refractory Non-Hodgkin's Lymphoma, Relapsed or Refractory Acute Lymphoblastic Leukemia, and Refractory or Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- GNC-038
- Conditions
- Non Hodgkin Lymphoma
- Sponsor
- Sichuan Baili Pharmaceutical Co., Ltd.
- Enrollment
- 47
- Locations
- 10
- Primary Endpoint
- Maximum tolerated dose (MTD) or maximum administrated dose (MAD)
- Status
- Active, not recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
An open, multicenter, Phase I clinical study to evaluate the safety, tolerability, pharmacokinetics/pharmacokinetics, and antitumor activity of GNC-038 quad-specific antibody injection in relapsed or refractory non-Hodgkin's lymphoma, relapsed or refractory acute lymphoblastic leukemia, and refractory or metastatic solid tumors.
Detailed Description
Phase Ia: To observe the safety and tolerability of GNC-038 in patients with relapsed or refractory non-Hodgkin lymphoma (R/R NHL)/relapsed or refractory acute lymphoblastic leukemia (R/R ALL), To determine the maximum tolerated dose (MTD) or maximum administration dose (MAD) and dose-limiting toxicity (DLT) of GNC-038 without MTD and recommend the dose for subsequent clinical studies. Phase Ib: To further observe the safety and tolerability of GNC-038 at the Phase Ia recommended dose to determine the Phase II recommended dose (RP2D).
Investigators
Eligibility Criteria
Inclusion Criteria
- •The participants could understand and sign the informed consent form, and must participate voluntarily.
- •No gender limit.
- •Age: ≥18 years old.
- •Expected survival time ≥ 3 months.
- •Histologically or cytologically confirmed non-Hodgkin's lymphoma or acute lymphoblastic leukemia.
- •Patients with relapsed refractory non-Hodgkin lymphoma (R/R NHL). Specifically, patients who relapsed for the first time and still progressed during second-line treatment; Patients with relapse after second-line or multiline therapy; Refractory patients showed no remission or progress after full dose and full cycle use of standard or current clinically commonly selected combination therapy regimen, and no remission or progress after replacement of second-line regimen; Patients with relapsed or refractory non-Hodgkin lymphoma who were determined to have no or no other treatments available/intolerant.
- •Relapsed or refractory acute lymphoblastic leukemia (R/R ALL), including: no response after more than 6 weeks of induction chemotherapy, or no response after 2 cycles of induction chemotherapy; A second or more recurrence of bone marrow; Or relapse for the first time after chemotherapy with no remission after at least 1 cycle of salvage therapy; Bone marrow recurrence after autologous stem cell transplantation (auto-HSCT); Patients with relapsed or refractory acute lymphoblastic leukemia were determined to have no or no other treatments/intolerant.
- •Patients with Philadelphia chromosome positive (Ph+) ALL who are intolerant to or fail to treat 1 and/or 2 generation tyrosine kinase inhibitors (TKI), or Ph+ALL who have a T315I mutation, do not require TKI salvage therapy.
- •For patients with NHL, there were measurable lesions in the screening period (lymph node lesions with any length ≥1.5cm or exodal lesions with any length \> 1.0cm); CLL/SLL: peripheral blood leukemia cells ≥5.0×109/L; Or lymph node lesions of any length ≥1.5cm; WM: IgM\> 2 x ULN.
- •For AITL and NK/T lymphoma, a membrane CD3 negative test is required.
Exclusion Criteria
- •Live virus vaccine (including attenuated live vaccine) was administered within 28 days prior to administration in this study.
- •Patients who received major surgery within 28 days prior to administration of the drug or planned to undergo major surgery during the study period (except for procedures such as puncture or lymph node biopsy).
- •Defined as ≥ Grade 3 pulmonary diseases according to NCI-CTCAE v5.0; Patients with present or history of interstitial lung disease (ILD).
- •Systemic serious infections occurred within 1 week before screening, including but not limited to severe pneumonia caused by fungi, bacteria and viruses, bacteremia or serious infectious complications.
- •Active tuberculosis.
- •People with active autoimmune disease, or a history of autoimmune disease, Including but not limited to Crohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis, Wegener syndrome, polyvasculitis granulomatosis, autoimmune hepatitis, systemic sclerosing disease, autoimmune vasculitis, autoimmune neuropathy (Guillain-Barre syndrome), etc. Exceptions include type I diabetes, hypothyroidism stable on hormone replacement therapy (including hypothyroidism caused by autoimmune thyroid disease), psoriasis or vitiligo that does not require systemic therapy, and B-cell autoimmune disease.
- •Non-melanoma skin cancer in situ, superficial bladder cancer in situ, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer, localized prostate cancer and other malignant tumors that were combined with other malignant tumors within 5 years prior to the first administration of the drug, and those that had been cured and had not recurred within 5 years were excluded.
- •HBsAg positive; HBcAb positive and HBV-DNA detection ≥ lower limit of detection value; HCV antibody positive and HCV-RNA≥ lower limit of detection value; HIV antibody positive.
- •Poorly controlled hypertension (systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 100 mmHg).
- •A history of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, degree III atrioventricular block, etc.; At rest, the QT interval was prolonged (QTc \> 450 msec in men or 470msec in women); Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months prior to initial administration; There is heart failure ≥II on the New York Heart Association (NYHA) cardiac function scale.
Arms & Interventions
Study treatment
The patients received intravenous infusion of GNC-038 for 1 cycle. After the completion of 2 cycles of treatment, participants with no unbearable ae could proceed to the 3rd and 4th cycles of treatment. After four cycles of treatment, participants with clinical benefits could also receive four additional cycles of the same dose.
Intervention: GNC-038
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD) or maximum administrated dose (MAD)
Time Frame: Up to 14 days after the first dose
In the dose increment stage, the highest dose whose estimated DLT rate is closest to the target DLT rate but does not exceed the upper bound of the equivalent interval of DLT rate is selected as MTD.
Dose limiting toxicity (DLT)
Time Frame: Up to 14 days after the first dose
The incidence and severity of adverse events (TEAE) during treatment were graded according to the National Cancer Institute Standard for Common Terminology for Adverse Events (NCI-CTCAE, v5.0).
Treatment-Emergent Adverse Event (TEAE)
Time Frame: Up to approximately 24 months
TEAE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally emerging, or any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition during the treatment of GNC-038. The type, frequency and severity of TEAE will be evaluated during the treatment of GNC-038.
The recommended dose for future clinical study
Time Frame: Up to 14 days after the first dose of GNC-038
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for phase II study, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation study of GNC-038.
Secondary Outcomes
- AUC0-inf: Area under the serum concentration-time curve from time 0 to infinity(Up to 14 days after the first dose of GNC-038)
- AUC0-t: Area under the serum concentration-time curve from time 0 to the time of the last measurable concentration(Up to 14 days after the first dose of GNC-038)
- Incidence and titer of ADA (Anti-drug antibody)(Up to approximately 24 months)
- Adverse Events of special interest (AESI)(Up to approximately 24 months)
- Cmax: Maximum serum concentration of GNC-038(Up to 14 days after the first dose of GNC-038)
- Css: Concentration of GNC-038 at steady state plateau(Up to 14 days after the first dose of GNC-038)
- T1/2: Half-life of GNC-038(Up to 14 days after the first dose of GNC-038)
- ORR (Objective Response Rate )(Up to approximately 24 months)
- DOR (Duration of Response)(Up to approximately 24 months)
- CL: Clearance in the serum of GNC-038 per unit of time(Up to 14 days after the first dose of GNC-038)
- Incidence and titer of Nab (Neutralizing antibody)(Up to approximately 24 months)
- DCR (Disease Control Rate)(Up to approximately 24 months)
- PFS (Progression-free Survival)(Up to approximately 24 months)
- Tmax: Time to maximum serum concentration (Tmax) of GNC-038(Up to 14 days after the first dose of GNC-038)