Solid tumor
Conditions
Interventions
Monotherapy escalation:Dose escalation part will explore dose levels
Patients with NON-G12C KRAS mutations (Arm a):Atamparib RP2D, Bid, oral, RP2D
Patients with G12C KRAS mutations and G12C KRAS inhibitors naive (Arm b):Atamparib RP2D, Bid, oral, RP2D
Patients with G12C KRAS mutations and G12C KRAS inhibitors pretreated (Arm c):Atamparib RP2D, Bid, oral, RP2D
Patients with KRAS wildtype (Arm d):Atamparib RP2D, Bid, oral, RP2D
Sponsors
Shanghai Eastern Hospital
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: 1. Eligible patients who were 18 years of age or older at the time of written informed consent. 2. Diagnosis: histologically confirmed unresectable advanced or metastatic NSCLC adenocarcinoma. 3. Archived tumor-tissue samples that were =1 year, sponsor approval was required) or fresh tumor-tissue biopsies had to be available. Documentation of test-confirmed KRAS mutation status was required at study entry (local testing was accepted). 5. Patients were required to have received at least one line of standard therapy and to have had failure of standard therapy, defined as radiographic tumor progression after the last dose. 6. Specific inclusion criteria: (1)For dose escalation, KRAS-mutated patients must not have received prior treatment with approved or investigational KRAS inhibitors, whether standard treatment options were limited or unavailable. The sponsor had the option to restrict enrollment to KRAS-mutant patients or allow enrollment of non-KRAS-mutant patients. (2) Dose-expansion cohort a: patients with non-G12C KRAS mutations who had not previously received any KRAS inhibitor; (3)Dose expansion cohort b: patients with G12C KRAS mutations who had not previously received KRAS G12C inhibitor therapy owing to lack of access to standard-of-care agents or no standard of care; (4)Dose-expansion cohort c: patients with G12C KRAS mutation previously treated with an approved KRAS G12C inhibitor; (5) Dose expansion cohort d: patients with wild-type KRAS. 7. Patients had to have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. 8. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1 (on a 6-point scale, with higher numbers indicating greater disability). 9. Life expectancy of at least 3 months. 10. Sign and date IEC-or IRB-approved informed consent indicating that the patient understands the neoplastic nature of his or her disease and has been made aware of the procedures to be followed, study nature of treatment, potential benefits, side effects, discomfort, risks, and alternative treatments. 11. All acute toxic effects (excluding alopecia) from any previous anticancer therapy have resolved to = grade 1 (NCI CTCAE v6.0) or baseline laboratory values 12. Patients had to use highly effective contraception or abstain from sex completely during the study. Male patients had to agree to use condoms during study treatment and for at least 3 months after the last IMP dose, even if they had undergone a successful vasectomy. Women of childbearing potential (WCBP), defined as sexually mature, not surgically sterilized, or not having had a natural menopause (i.e., menstruating at any time in the past 12 consecutive months) for at least 12 consecutive months, had to agree to use highly effective contraception or complete abstinence during treatment and for 6 months after the last dose of IMP. Because Atamparib has the potential to induce CYP3A4, women of childbearing potential should not rely on hormonal contraceptives as an effective method of contraception. 13. Male patients had to agree not to donate sperm during study treatment and for at least 3 months after the last dose of IMP, and female patients had to agree not to donate eggs during study treatment and for at least 6 months after the last dose of IMP. 14. Be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study instructions or procedures.
Exclusion criteria
Exclusion criteria: Patients were not eligible if they met any of the following criteria: 1. Histologically confirmed non-adenocarcinoma NSCLC. Patients with tumors that were histologically confirmed to be mixed types were also ineligible. 2. Prior oncogenic driver mutations other than KRAS that have been inadequately treated with marketed standard-of-care agents (including, but not limited to, EGFR or ALK mutations). The sponsor had the option to rule out other driver mutations. 3. Other interventional clinical trials have been enrolled at present. 4. Currently receiving other antineoplastic drugs or devices. 5. Previous antineoplastic therapy within 2 weeks or five half-lives, whichever was longer, before the first dose or use of an immune checkpoint inhibitor in a previous line of therapy within 1 month before the first dose. 6. Major surgery was performed within 4 weeks before the first dose. 7. Patients with prior extensive radiotherapy affecting at least 20% of bone marrow or radiation dose > 30 Gy to the lung within 6 months before the first dose. 8. Use full-dose anticoagulation unless the international normalized ratio (INR) or aPTT is within the therapeutic limit (according to center medical standards) and the patient has been receiving a stable dose of anticoagulant for at least 2 weeks before enrollment. 9. Herbal or traditional Chinese medicine (TCM) with anticancer purpose or affecting study drug metabolism were used during the study. These include, but are not limited to: from the screening period, St. John's wort, cannabis (including "medical cannabis"), Kava pepper, ephedrine (Epstein-huang), ginkgo biloba extract, DHEA, yohimbe, saw palmetto, black seed grass and ginseng, grapefruit, grapefruit juice, pomegranate juice, starfruit, citrus fruit or orange jam made from lime (Seville orange). 10. Potent inhibitors or inducers of CYP3A4, P-glycoprotein (Pgp), or breast cancer resistance protein (BCRP) were required within 2 weeks before or during the study. Individual cases could be decided after discussion with the investigators and medical monitors. 11. Patients required narrow-window therapy with CYP2C9, 2C19, or 3A4 substrates during the study. Individual cases could be decided after discussion with the investigators and medical monitors. 12. Patients required narrow-window drugs with multidrug and toxic compound efflux protein (MATE) 1, MATE2K, organic anion transport polypeptide 1B3 (OATP1B3), or BCRP substrates during the study period. Individual cases could be decided after discussion with the investigators and medical monitors. 13. History of interstitial lung disease, or pulmonary inflammation requiring adjuvant treatment with oral or intravenous sterols, or associated pulmonary disease as considered by the investigator. 14. Systemic immunomodulatory therapy such as corticosteroids (prednisone equivalent dose > 10 mg/ day), cyclosporine and tacrolimus, or radiotherapy within 28 days before day 1 of cycle 1. 15. Pregnant or lactating women. 16. Known allergy to any component of the Atamparib preparation. 17. Active, life-threatening, or clinically significant, uncontrolled systemic infection (bacterial, fungal, or viral, including HIV positive or HBV or HCV infection, as confirmed by a local research site or see Appendix 3 in Section 19.3) that is known to require systemic therapy; Hiv-positive persons were allowed to enroll if their viral load became undetectable after more than 6 months of anti-HIV drug control. 18. Known active ga
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall safety profile of atamparib characterized by type, frequency and severity (graded using CTCAE v6.0), duration of AEs, first cycle DLTs, electrocardiogram (ECG) and laboratory abnormalities, and relationship of AEs to the study treatment.; | — |
Secondary
| Measure | Time frame |
|---|---|
| To evaluate anti-tumor efficacy of atamparib;To evaluate the pharmacokinetics of atamparib administered as monotherapy; | — |
Countries
China
Contacts
Public ContactCaicun Zhou
Shanghai Eastern Hospital
Outcome results
None listed