Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: The Study to Evaluate JS001 in Patients With Advanced GC, ESCC, NPC, HNSCC

Summary: The purpose of this study is to preliminarily evaluate anti-tumor activity of a Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Infusion (JS001) in treating advanced gastric adenocarcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma and to determine the recommended phase II dose (RP2D)

Detailed description: Overall Design:
  This study is a phase Ib/II clinical study of a Recombinant Humanized Anti-Programmed Death Antibody 1 (PD-1) Monoclonal Antibody for infusion. It is a multicenter, open-label clinical study to investigate the preliminary efficacy and safety of JS001 at 4 indications including gastric adenocarcinoma (GC), esophageal squamous cell carcinoma (ESCC), nasopharyngeal carcinoma (NPC), and head and neck squamous cell carcinoma (HNSCC), which have unique unmet clinical need in China. Subjects will be eligible for this study after they fulfill the inclusion criteria and exclusion criteria. Subjects diagnosed as the gastric adenocarcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, or head and neck squamous cell carcinoma will receive treatment at the dose of 3 mg/kg. If one certain indication cannot reach the predefined study endpoints under the dose of 3 mg/kg, enrollment of patients will be expanded to 10mg/kg group. Meanwhile, subject to the safety and pharmacokinetic data from other dose groups observed in other ongoing or coming phase I studies, this study may explore to other dose groups and determine the RP2D of relevant indication.
  To add new dose group(s), approval from Data and Safety Monitoring Committee (DSMC) and Ethics Committee for local study site should be obtained before initiation of subject enrollment.
  Study Treatment:
  This study is planned to conduct the 3 mg/kg dose group study at first. After enrollment, the subjects will be administered every 2 weeks (Q2W) with 4 weeks as a cycle, until absence of further benefits, acceptable toxicity, investigator decision, consent withdrawal or death.
  If patient experiences 1st onset of disease progression and investigator judges that patient will obtain clinical benefit from the study treatment, patient can continue the study treatment after the discussion between investigator and medical monitor from sponsor or authorized CRO and approval is obtained afterwards. If the subject develops 2nd disease progression after 1st disease progression, he/she should permanently withdraw from the study treatment.
  Tumor Assessment:
  During the study, tumor response assessment will be conducted every 8 weeks in the first year according to RECIST 1.1 criteria, and every 12 weeks thereafter. Tumor response assessments will also be evaluated according to irRC at them same frequency with RECIST 1.1.
  Pharmacokinetics:
  At least 10 of patients (no limit for indication) in 3 mg/kg dose group at the assigned study sites, should complete serial pharmacokinetic blood sampling at the first 3 cycles. If a subject cannot complete the scheduled sample collection due to any cause, another subject should be substituted. The schedule of pharmacokinetic blood sampling is referred to Appendix 2. If other dose groups are opened during the study, at least 10 subjects from each dose group should participate in serial pharmacokinetic blood sampling.
  Acquisition of Tumor Tissue Specimen:
  Patients with esophageal squamous cell carcinoma, gastric adenocarcinoma (including adenocarcinoma at esophageal-gastric conjunction) or head and neck squamous cell carcinoma must provide tumor tissue specimens prior to enrollment to detect the expression of PD-L1. Only the patients with positive PD-L1 expression are eligible to the study. Subjects with nasopharyngeal carcinoma must provide tumor tissue specimens prior to enrollment for future use in subsequent exploratory researches.
  If the response is verified as partial response (PR) and/or progression of disease (PD) for subjects in nasopharyngeal carcinoma group or head and neck squamous cell carcinoma group and tumor tissues could be obtained, these subjects can voluntarily participate in a subgroup study of this study. They will provide tumor tissues for exploratory research in correlation between tumor marker and anti-tumor response level. All the tumor tissue specimens provided will be sent to designated central laboratory for further evaluation
  End of Study:
  The primary endpoint of the study is ORR. The study will be complete after 12 months of last subject first dosing and data analysis will be conducted at the same time. If by then there are still some subjects receiving treatment of study drug, these subjects will be transferred to an expansion study to continue treatment of study drug until occurrence of no more clinical benefits, unacceptable toxicity, investigator deciding to end the treatment, withdrawal of inform consent or death.

Eligibility: Inclusion Criteria:
  1. Fully understand the study and sign the Informed Consent Form (ICF) voluntarily;
  2. Patients with histologically and/or cytologically diagnosed as advanced gastric adenocarcinoma (including adenocarcinoma at esophageal-gastric conjunction), esophageal squamous cell carcinoma, nasopharyngeal carcinoma, head and neck squamous cell carcinoma, and who meet the following conditions:
  -  Patients with gastric adenocarcinoma must have received at least one line of treatment for advanced gastric adenocarcinoma and have tumor progression documented or be intolerable to the current chemotherapy regimen. Patients who have recurrence or metastasis within 6 months after completion of adjuvant or neoadjuvant chemotherapy are eligible to this study;
  -  Patients with esophageal squamous cell carcinoma must have received at least one line of treatment for advanced esophageal squamous cell carcinoma (including but not limited to anticancer drug treatment or concomitant radio-chemotherapy) and have tumor progression documented or be intolerable to the current chemotherapy regimen. Patients who have recurrence or metastasis within 6 months after completion of adjuvant or neoadjuvant therapy (including but not limited to chemotherapy or concomitant radio-chemotherapy) accompanied by the radical operation are eligible to this study;
  -  Patients with nasopharyngeal carcinoma or head and neck squamous cell carcinoma who have received at least one line of treatment for advanced nasopharyngeal carcinoma or head and neck squamous cell carcinoma (including but not limited to anticancer drug treatment or concomitant radio-chemotherapy) and have tumor progression documented or be intolerable to other current chemotherapy regimens. Patients with recurrence or metastasis within 6 months after completion of adjuvant or neoadjuvant concomitant radio-chemotherapy are eligible to this study.
  3. Have at least one measurable lesion (according to RECIST 1.1); Note: Lesion with radiotherapy treated previously can't be regarded as a target lesion, unless which has definite progressed after radiotherapy.
  4. Agree to provide the archived tumor tissue specimens or have biopsy to collect tumor tissues in order to send them t for PD-L1 IHC measurement in central lab. For patients with gastric adenocarcinoma, esophageal squamous cell carcinoma, or head and neck squamous cell carcinoma, only those with positive PD-L1 expression (positivity is defined as PD-L1 expression > 1% by employing Spring Bioscience PD-1/L1 IHC test) can be included in this study;
  5. Male or female aged between 18 to 75 years of old;
  6. ECOG score: 0-1;
  7. Estimated survival duration ≥ 3 months;
  8. The laboratory examination results obtained within 7 days prior to enrollment must meet the following criteria:
  1. Neutrophil ≥1.5×109/L;
  2. Platelet ≥75×109/L;
  3. Hemoglobin ≥90 g/L (without infusion of concentrated red blood cells within 2 weeks);
  4. Serum creatinine ≤ 1.5× ULN, or creatinine clearance > 50 mL/min;
  5. Total serum bilirubin ≤ 1.5×ULN (total bilirubin ≤ 3×ULN are acceptable for patients with Gilbert syndrome);
  6. Both AST and ALT ≤ 2.5×ULN; ALT and AST≤5×ULN are acceptable for patients with liver metastasis;
  9. Negative serum pregnancy result must be confirmed in women of childbearing potential within 21 days prior to enrollment and agree to take effective contraception measures during study treatment period and within 28 days after the end of study treatment. Women of childbearing potential are defined as women with sexual maturity who meet any of the following conditions: 1) have no hysterectomy or bilateral oophorectomy; 2) without natural menopause more than consecutive 24 months (patients with menopause after cancer treatment may also have childbearing potential) (i.e. menstruation occurred at any time during the previous consecutive 24 months).
  Exclusion Criteria:
  1. Known to be allergic to citric acid monohydrate, dihydrate sodium citrate, mannitol or polysorbate (components of the investigational drug);
  2. Received anti-tumor treatment with cytotoxic chemical drugs, biological drugs (e.g. monoclonal antibody), immunotherapy (e.g. interleukin 2 or interferon), or other study drugs within 4 weeks prior to enrollment, or are still within 5 half-lives of this kind of drugs;
  3. Received tyrosine kinase inhibitor treatment within 2 weeks prior to enrollment;
  4. Received radiotherapy within 4 weeks prior to enrollment, or received treatment with radioactive drugs within 8 weeks prior to enrollment. However, local palliative radiotherapy for bone metastasis lesions should be excluded;
  5. Received major surgical operation within 4 weeks prior to enrollment or have not completely recovered from the prior operation (For the definition of major surgical operation, please refer to the Level 3 and Level 4 operations stipulated in the Management of Clinical Application of Medical Technology enforced on May 1, 2009);
  6. Toxicity due to any previous anticancer treatment has not recovered to CTCAE [Version 4.03] Grade 0-1, excluding the following conditions:
  1. Alopecia;
  2. Pigmentation;
  3. Peripheral nerve toxicity has recovered to ≤ CTCAE Grade 2;
  4. Long-term toxicity related to radiotherapy won't be fully recovered as judged by investigator.
  7. Have central nervous system metastasis with clinical symptoms (e.g. brain edema, demand of hormone intervention, or progression of brain metastasis) and/or carcinomatous meningitis. Patients received treatment for brain or meningeal metastasis previously can be included if they have remained stable clinically for at least 2 months and systemic glucocorticoid treatment (Prednisone with dose >10 mg/day or other equivalent formulations) has been discontinued for more than 4 weeks;
  8. Patients with nasopharyngeal carcinoma or head and neck squamous cell carcinoma are found to have necrotic lesions by examination within 4 weeks prior to enrollment, for which there is a potential risk of massive hemorrhage as judged by investigator;
  9. Received systemic or local glucocorticoid therapy within 4 weeks prior to enrollment;
  10. Had/Have other malignant tumor previously or currently (expect for effectively controlled non-melanoma skin basal cell carcinoma, breast/cervix carcinoma in situ, and other malignant tumors which were effectively controlled without treatment over the past 5 years);
  11. Patients having any active autoimmune disease or history of autoimmune disease (including but not limited to interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, nephritis, hyperthyroidism or hypothyroidism. Patients with vitiligo or asthma (in childhood) was completely resolved and without need of any intervention in adulthood can be included. Patients with asthma which needs bronchodilator for medical intervention cannot be included);
  12. Have been treated by anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody or anti-CTLA-4 antibody (or any other antibody which acts on T-cell co-stimulatory or checkpoint pathway) previously;
  13. Patients are diagnosed as active tuberculosis (TB) and receiving anti-tuberculosis therapy or used to have anti-tuberculosis therapy within 1 year prior to screening;
  14. Have concomitant diseases that require long-term treatment with immunosuppressive drugs, or need corticosteroids at an effective immunosuppressive dose for systemic or local treatment purpose;
  15. Received any anti-infection vaccine (e.g. influenza vaccine, varicella vaccine, etc.) within 4 weeks prior to enrollment;
  16. Pregnant or lactating women
  17. HIV positive;
  18. HBsAg positive with HBV DNA copies detected as positive (quantitative measures ≥ 1000 cps/ml);
  19. Positive for chronic Hepatitis C in blood screening test (HCV antibody positive);
  20. Any other clinical significant disease or condition, as evaluated by the investigator, may affect the protocol compliance, or inform consent process or not suitable to participate into this clinical trial.

Relevance to patient case: not relevant