Trial Title:
Propranolol Hydrochloride in Combination With Sintilimab and Platinum-based Chemotherapy for Treatment of Advanced Non-small Cell Lung Cancer
NCT ID:
NCT05979818
Condition:
Non Small Cell Lung Cancer
Propranolol
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Propranolol
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Propranolol hydrochloride
Description:
10 mg, PO, BID, for up to 2 years until disease progression/intolerable
toxicity/withdrawal of informed consent.
Arm group label:
Propranolol hydrochloride in combination with sintilimab and platinum-based chemotherapy
Other name:
Inderal
Intervention type:
Drug
Intervention name:
Sintilimab
Description:
intravenous infusion (IV), 200 mg, Day1, Q3W, for up to 2 years until disease
progression/intolerable toxicity/withdrawal of informed consent.
Arm group label:
Propranolol hydrochloride in combination with sintilimab and platinum-based chemotherapy
Intervention type:
Drug
Intervention name:
Chemotherapy
Description:
Platinum-based chemotherapy:
For non-squamous cell carcinoma options: carboplatin/cisplatin + pemetrexed; For squamous
cell carcinoma: carboplatin/cisplatin + paclitaxel/gemcitabine. Carboplatin: IV, AUC 5,
Day1, Q3W; Cisplatin: IV, 75 mg/m2, Day1-3, Q3W; Pemetrexed: IV, 500 mg/m2, Day1, Q3W;
Paclitaxel: IV, 175 mg/m², Day1, Q3W; Albumin-bound paclitaxel: IV, 100 mg/m², Day1, 8,
15; or 260 mg/m2, Q3W; Gemcitabine: IV, 1000mg/m2, Day1, 8, Q3W; After 4-6 cycles of
sintilimab and platinum-based chemotherapy, the patients of non-squamous cell carcinoma
will be received with sintilimab and pemetrexed for maintenance therapy, for up to 2
years until disease progression/intolerable toxicity/withdrawal of informed consent.
Arm group label:
Propranolol hydrochloride in combination with sintilimab and platinum-based chemotherapy
Summary:
This study is a prospective single-center Phase I clinical study in patients with
EGFR/ALK/ROS1 driver oncogene negative, and advanced or metastatic NSCLC. This study is
to evaluate the efficacy and safety preliminarily in a small-size of propranolol
hydrochloride in combination with sintilimab and platinum-based chemotherapy in
first-line therapy. Propranolol hydrochloride is a beta- adrenergic blocking agent which
is associated with augment of immune cell responses. Propranolol hydrochloride may
improve the responses of immune checkpoint inhibitors in treating patients with advanced
NSCLC.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Sign a written informed consent prior to any research-related procedure
- Age ≥18 years and ≤ 75 years old
- ECOG PS score of 0-1
- Expected survival time ≥ 12 weeks
- Patients with histologically or cytologically confirmed non-localizable stage
IIIB-IIIC, stage IV non-small cell lung cancer (International Association for the
Study of Lung Cancer and the Joint Committee on the American Classification of
Cancers, 8th edition). Patients with unresectable IIIB-IIIC include recurrent and
primary unresectable (surgery and radical concurrent chemoradiotherapy), and stage
IV includes primary or recurrent stage IV but without prior systemic therapy for
advanced/metastatic disease.
- Chemotherapy and chemoradiotherapy are permitted as neoadjuvant/adjuvant treatment
as long as the treatment is completed at least 12 months prior to the diagnosis of
advanced or metastatic disease
- There must be no EGFR gene-sensitive mutation, ALK gene fusion or ROS1 gene fusion
in non-squamous carcinoma
- At least one imaging measurable lesion according to the criteria for the evaluation
of the efficacy of solid tumors (RECIST version 1.1). A lesion located in the field
of exposure to previous radiotherapy is considered measurable if progression is
confirmed (within 28 days prior to the first treatment)
- Subjects with brain metastases who are asymptomatic or whose symptoms have
stabilized with local treatment are permitted to be enrolled, provided that the
subject meets the following criteria:
1. Have a measurable lesion outside the CNS.
2. No CNS symptoms or no worsening of symptoms for at least 2 weeks.
3. No glucocorticoid therapy is required, or glucocorticoid therapy has been
discontinued within 7 days prior to the first dose, or the glucocorticoid
dosage has been stable and reduced to less than 10 mg/day of prednisone (or
equivalent dose) within 7 days prior to the first dose
- Meet the following laboratory indicators (within 14 days before the first
treatment):
1. Blood routine examination: absolute neutrophil count ≥ 1.5 x 10^9/L; platelet
count ≥ 100 x 10^9/L; hemoglobin level ≥ 9.0 g/dL (no blood transfusion or
erythropoietin-dependent administration within 7 days).
2. Liver function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN);
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN
in the absence of hepatic metastases; ALT or AST ≤ 5 × ULN in the case of
patients with hepatic metastases.
3. Renal function: serum creatinine (Cr) ≤1.5 times ULN or Cr clearance ≥60 mL/min
(Cockcroft-Gault formula), and urine routine test results show urine protein
(UPRO) <2+ or 24-hour urine protein quantification <1g.
4. Coagulation: International Normalized Ratio (INR) ≤ 1.5 times ULN or
Prothrombin Time (PT) ≤ 1.5 times ULN within 7 days prior to study treatment;
if the subject is receiving anticoagulant therapy, as long as the PT is within
the range of the anticoagulant drug
- Heart function: the New York heart association (NYHA) classification < 3;Left
ventricular ejection fraction（LVEF）≥ 50%; Baseline ECG showed no PR interval
lengthened or atrioventricular block
- For female subjects of childbearing potential, a negative urine or serum pregnancy
test should be obtained within 3 days prior to receiving the first dose of study
drug (Day 1 of Cycle 1). If a negative urine pregnancy test result cannot be
confirmed, a blood pregnancy test will be requested. Females not of childbearing
potential are defined as being at least 1 year postmenopausal or having undergone
surgical sterilization or hysterectomy; if conception is at risk, all subjects (male
or female) are required to use contraception with an annual failure rate of less
than 1% throughout the treatment period up to 120 days after the end-of-treatment
administration of study drug (or 180 days after the end-of-study drug
administration)
Exclusion Criteria:
- Concurrent participation in another interventional clinical study or receipt of
another investigational drug, unless participating in an observational clinical
study
- Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody
therapy, or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways
- Systemic therapy with proprietary Chinese medicines with anti-tumor indications or
immunomodulatory drugs (including thiopeptides, interferons, interleukins, except
those used locally for the control of hydrothorax or ascites) within 2 weeks prior
to the first dose
- Current use of oral or intravenous beta-blockers (e.g., atenolol, bisoprolol,
carvedilol, labetalol, metoprolol, nadolol, sotalol, etc.) cannot be safely switched
to a non-beta-blocker
- There are contraindications to the use of beta-blockers:
1. Hypersensitivity to any of the components of the product.
2. Bronchial asthma or risk of bronchospasm.
3. Ketoacidosis and metabolic acidosis.
4. Severe or symptomatic bradycardia (resting heart rate ≤55bpm), atrioventricular
block (degrees II and III), sinus block, sick sinus node syndrome.
5. Cardiogenic shock
6. Right heart insufficiency due to pulmonary hypertension.
7. Congestive heart failure (class III or IV).
8. Hypotension (systolic blood pressure < 100 mmHg).
9. Prolonged fasting.
10. Severe peripheral circulatory failure (e.g., gangrene).
11. Symptomatic peripheral arterial disease or Raynaud's syndrome, untreated
pheochromocytoma.
12. Unstable angina or variant angina.
13. Patients on rizatriptan benzoate.
14. Severe asthma or chronic obstructive pulmonary disease (COPD)
15. Uncontrolled type I or type II diabetes mellitus (glycosylated hemoglobin
[HbA1C] > 8.5 or fasting blood glucose > 160 mg/dl at screening).
16. Current use or within the last 2 years of a non-dihydropyridine calcium channel
blocker (NDCCB)
- Hepatic encephalopathy, hepatorenal syndrome or Child-Pugh class B or more severe
cirrhosis
- Tumor-related intestinal obstruction (within 3 months prior to the signing of the
informed consent) or history of inflammatory bowel disease or extensive bowel
resection (partial colectomy or extensive small bowel resection with chronic
diarrhea), Crohn's disease, ulcerative colitis
- Completion of palliative radiotherapy within 7 days prior to the first dose of study
drug
- With clinically active diverticulitis, abdominal abscess, gastrointestinal
obstruction
- History of psychotropic substance abuse or addiction
- Known hypersensitivity to the active ingredients or excipients of the study drug
- Known history of primary immunodeficiency or undergoing systemic glucocorticoid
therapy or any other form of immunosuppressive therapy
- Use of immunosuppressive drugs, excluding topical glucocorticoids by nasal,
inhalational or other routes or physiological doses of systemic glucocorticoids
(i.e., no more than 10 mg/day of prednisone or an equivalent dose of other
glucocorticoids), or use of hormones for the prevention of contrast sensitization,
within 4 weeks prior to the first dose of study treatment
- Failure to recover adequately from any intervention-induced toxicity and/or
complications (≤ grade 1 or baseline, excluding weakness or alopecia) prior to
initiation of treatment
- Receipt of live attenuated influenza vaccine within 4 weeks prior to the first dose
of study treatment or planned for the duration of the study (inactivated injectable
viral vaccine against seasonal influenza is permitted up to 4 weeks prior to the
first dose; however, live attenuated influenza vaccine is not permitted)
- Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the
first dose of study treatment or anticipation of major surgery during study
treatment; laparoscopic exploratory surgery within 2 weeks prior to the first dose
of study treatment
- Known symptomatic CNS metastases and/or carcinomatous meningitis. Subjects with
previously treated brain metastases may be enrolled in the trial if they are
clinically stable (no evidence of imaging progression for at least 4 weeks prior to
the first dose of the experimental treatment, no evidence of new brain metastases or
increase in size of pre-existing brain metastases as confirmed by repeat imaging)
and do not require steroid therapy for at least 14 days prior to the first dose of
the experimental treatment. This exception does not include carcinomatous
meningitis, which should be excluded regardless of whether it is clinically stable.
- Presence of clinically uncontrolled pleural effusion or ascites (subjects may be
recruited who do not require drainage of the effusion or who do not have a
significant increase in the effusion after 3 days of cessation of drainage)
- Patients with bone metastases at risk of paraplegia
- Known or suspected autoimmune disease or history of such disease within the last 2
years (patients with vitiligo, psoriasis, alopecia areata or Graves' disease not
requiring systemic treatment within the last 2 years, hypothyroidism requiring only
thyroid hormone replacement therapy, and type I diabetes mellitus requiring only
insulin replacement therapy may be enrolled)
- Known to have active tuberculosis.
- A history of allogeneic organ transplants and allogeneic hematopoietic stem cell
transplants is known
- Known history of human immunodeficiency virus (HIV) infection (HIV-positive)
- Known acute or chronic active hepatitis B virus (HBsAg-positive and HBVDNA viral
load ≥200 IU/mL or ≥10^3 copies/mL) or acute or chronic active hepatitis C virus
(HCV antibody-positive and HCV RNA-positive)
- Active syphilis infection requiring treatment
- Suffer from interstitial lung disease requiring steroid hormone therapy
- Serious infections that are active or poorly controlled clinically
- Severe cardiovascular disease (e.g., myocardial infarction, arterial
thromboembolism, cerebrovascular thromboembolism); angina pectoris requiring
treatment; symptomatic peripheral vascular disease; NYHA cardiac class 3 or 4
congestive heart failure; or uncontrolled ≥class 3 hypertension (diastolic blood
pressure ≥100 mm Hg or systolic blood pressure ≥160 mm Hg) despite antihypertensive
treatment
- History of other primary malignancies within 5 years, except：
1. malignancies that have been in complete remission for at least 2 years prior to
enrolment and for which no other treatment was required during the study
period.
2. adequately treated non-melanoma skin cancer or malignant nevus with no evidence
of disease recurrence.
3. adequately treated carcinoma in situ without evidence of disease recurrence
- Female patients who are pregnant or breastfeeding
- Other acute or chronic medical conditions, psychiatric disorders, or abnormal
laboratory test values that may result in increased risk associated with study
participation or administration of study medication, or interfere with the
interpretation of study results, and that, in the investigator's judgement, classify
the patient as ineligible for participation in this study.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
December 31, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Second Xiangya Hospital of Central South University
Agency class:
Other
Collaborator:
Agency:
Innovent Biologics (Suzhou) Co. Ltd.
Agency class:
Industry
Source:
Second Xiangya Hospital of Central South University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05979818
