Clinical Outcomes of Intravenous Vitamin C Synergy With Tyrosine Kinase Inhibitor in Lung Adenocarcinoma Patients With Epidermal Growth Factor Receptor Mutations
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Clifford Hospital, Guangzhou, China

Clinical outcomes of intravenous vitamin C synergy with Tyrosine kinase
inhibitor in lung adenocarcinoma patients with epidermal growth factor receptor
mutations
November 14, 2018

Study Protocol and Statistical Analysis Plan
Background:
Vitamin C (VitC) infusion are widely used by integrative and complementary cancer
practitioners for many years. In the last 10 years, many studies have shown that
pharmacological concentrations of VitC can selectively kill tumor cells. A series of in
vitro experiments [1], animal experiments [2-4] and Phase I-II clinical trials [5-7]
have successively confirmed that VitC at pharmacological concentrations has the
effect of inhibiting the growth of various tumors, including lung cancer.
Our Phase I clinical study, “The safety and pharmacokinetics of high dose intravenous
ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with
stage III -IV non-small cell lung cancer", confirmed the safety of high-dose vitamin C
in combination with deep hyperthermia in advanced non-small cell lung cancer, the
concentration is as high as 1.5g/kg.d, 3 times a week. There were no significant
adverse reactions. And it can significantly improve the quality of life (QoL). Our
Phase II clinical trial in 2018 confirmed that IVC + mEHT treatment can significantly
improve QoL, prolonge progression free survival (PFS) and overall survival (OS), and
moderate cancer-related inflammation in advanced NSCLC patients. The article is
already in the submission stage.
Recently we noticed that patients with epidermal growth factor receptor (EGFR)
mutation who were taking tyrosine kinase inhibitor (TKI) with intravenous VitC every
week had a relatively longer drug resistance time in our oncology center. We believe
that it is necessary to observe whether intravenous VitC simultaneously with TKI can
prolong the time of drug resistance in patients with EGFR mutations.
Objectives:
The purpose of this study was to investigate the effect of intravenous VitC in
combination with TKI on the tumor size, QoL, PFS and OS in lung adenocarcinoma
patients with EGFR mutation
Inclusion Criteria:

Primary non-small cell lung cancer (adenocarcinoma) with EGFR mutations on
exons 19 and 21.

18 years old to 75 years old.

During the trial, patients were prescribed TKI (received initial treatment within 2
months,
or
change
medication
within
2
months)
and
did
not
receive
chemotherapy or radiotherapy at the same time.

Eastern Cooperative Oncology Group(ECOG) performance status are 0 to 2.

Expected survial over 3 months.

Household registration is Guangdong Province.
Exclusion Criteria:

Co-morbid conditions that affect survival: end stage congestive heart failure,
unstable
angina,
myocardial
infarction
(within
the
past
6
weeks),
and
uncontrolled blood sugars of greater than 300 mg/dL, known chronic active
hepatitis or cirrhosis.

Glucose-6-phosphate
dehydrogenase
deficiency
(G6PD)
(a
relative
contraindication).


Patients who are allergic to VitC.

Patients with HIV and other infectious diseases.

Patients who are taking anticoagulants and have coagulopathy;

Combine dysfunction of important organs such as heart, lung, liver and kidney;

Patients with impaired renal function (serum creatinine content > 1.2 mg/dL)

Compromised liver function with evidence of Serum total bilirubin content, ALT
and AST> 2 times normal reference value.

Pregnant or lactating female.

Smoking and alcohol abuse patients;

Anti-infective treatment is required for systemic or localized serious infections;

Patients with hyperuric acidosis (normal: 91-456 μmol / 24h (8-40mg / 24h));

Wilson's disease.

Evidence of significant psychiatric disorder by history or examination that would
prevent completion of the study or preclude informed consent.

Any condition that impairs the patients' ability to swallow, which impairs drug
absorption or drug kinetic parameters, including any kind of gastrointestinal
resection or surgery;

History of surgery of visceral organs within 6 weeks before the trial.
Study design:
Experimental period: 12.05.2018~31.12.2019
Method:
In experimental group:75 patients received a weekly intravenous Vitamin C injection
(dose: 30 g / time, once a week, treatment termination when the disease progress is
confirmed) in combination with daily TKI; In the control group:75 patients received
only TKI daily. (dose: Osimertinib 80 mg/d, or Tarceva 150 mg/d, or Iressa 0.25 g/d.)
Outcome:
Primary outcome was PFS. Secondary outcome include: OS, QoL, tumor size.
Observations and assessments:
To evaluate the effects of the above treatments on patient safety, tumor size, tumor
markers, inflammatory factor levels, quality of life, progression-free survival and
overall survival time. General information was collected before and after treatment,
and the QoL was assessed on the quality of life questionnaire (QLQ-C30) scale.Chest
CT enhancement, brain MRI, liver color Doppler ultrasound, adrenal gland ultrasound,
blood test for liver and kidney function, blood and urine routine, tumor markers,
tumor necrosis factor, interleukin-6 level were checked every month.
Statistical methods:
The effect of treatment on PFS, OS was analyzed by using Kaplan-Meier probability
estimates. Comparison of tumor markers and immune factors was performed using t-
test.
Key issues to be addressed:
To explore whether intravenous VitC can prolong resistance time of TKI on lung
adenocarcinoma patients with EGFR mutations. To observe whether the combination
treatment can benefit NSCLC patients.
Expected results:

Intravenous VitC in combination with TKI can significantly prolong the time of drug
resistance, improve the quality of life, and have a positive effect on the prognosis of
lung adenocarcinoma patients with EGFR mutations.
Safety measures and emergency plan:
Diarrhea, rash, liver dysfunction and other adverse reactions may occur during the
treatment, but the above reactions will be eliminated under the doctor's treatment. If
patients experience any discomfort during the study, or if there is a new change in the
condition, or any unforeseen circumstances, whether or not related to treatment,
patients should promptly notify their doctor, who will make a judgment and medical
treatment. If the condition of the disease changes to a certain standard (if the
condition progresses), the trial may be terminated earlier after discussion by the
research group.
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