A Study of NB003 in Patients with Advanced Malignancies

This a A Phase 1, Open-label, Multicenter Study to Assess the Safety, Tolerability, and Pharmacokinetics of NB003 in Subjects with Advanced Malignancies

This is a phase 1, open-label, multicenter study of NB003 which comprised of a dose escalation phase to determine the MTD or maximum administered dose (MAD), and the RP2D and a dose expansion phase to further explore the safety, PK and efficacy of NB003.

The dose escalation phase will enroll patients with advanced gastrointestinal stromal tumor (GIST) who have progressed on or had an intolerability to imatinib and other standard of cares (SoCs) or refused other SoCs, and patients with advanced malignancies other than GIST that harbors KIT or PDGFRα gene alterations who have relapsed or have refractory disease without an available effective therapy. The number of patients to be enrolled during the dose escalation part will vary depending on the underlining dose-toxicity curve and the number of dose levels tested prior to reaching MTD or MAD. After the MTD or MAD has been determined, based on emerging safety/PK data, one or more putative RP2D(s) will be explored in dose escalation phase with approximately 15 patients for each provisional RP2D(s) to establish the RP2D for dose expansion phase. This step will be regarded as RP2D confirmation part of dose escalation phase.

In the dose expansion phase, additional patients will be enrolled to further explore the safety, tolerability, PK, efficacy and biological activity of NB003 in specific disease cohorts, including GIST and other malignancies harboring genomic alterations of KIT or PDGFRα. Dose expansion phase is planned to investigate NB003 at the RP2D determined from dose escalation phase.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females of any race ≥18 years age.
2. Histologically-confirmed diagnosis of unresectable, relapsed or metastatic GIST or other advanced malignancies.

   1. For dose escalation phase:

      * GIST patients must have progressed on or had an intolerability to imatinib and other SoCs or refused other SoCs.
      * Patients with an advanced solid tumor other than GIST must have relapsed or had refractory disease without an available effective therapy and harbor KIT or PDGFRα gene alterations (central laboratory confirmation is not required for screening).
   2. For dose expansion phase:

   Cohort 1: GIST patients with KIT or PDGFRα gene mutations, must have progressed on or been intolerant to at least imatinib, sunitinib, regorafenib and ripretinib (≥ fifth line therapy setting); Cohort 2a: GIST patients with KIT or PDGFRα gene mutations, must have progressed on or been intolerant to imatinib and sunitinib, and who have not received additional systemic therapy for advanced GIST (third line therapy setting); Cohort 2b: GIST patients with KIT or PDGFRα gene mutations, must have progressed on or been intolerant to imatinib, sunitinib and regorafenib, and who have not received additional systemic therapy for advanced GIST (forth line therapy setting); Cohort 3: GIST patients with KIT or PDGFRα gene mutations, must have progressed on or been intolerant to imatinib and have not received additional systemic therapy for advanced GIST (second line therapy setting); Cohort 4: GIST patients with PDGFRα exon 18 mutation and must have progressed on or been intolerant to avapritinib; in the countries/regions where avapritinib is not SoC, avapritinib-naïve patients can be enrolled; Cohort 5: Unresectable or metastatic melanoma patients with demonstrated evidence for KIT gene mutation and/or amplification, must have progressed on or been intolerant to SoCs; Cohort 6: Patients with other advanced malignancies other than GIST or melanoma which must be relapsed or refractory without an available effective therapy and harbor KIT or PDGFRα gene alterations.
3. For dose expansion phase: at least one measurable lesion per RECIST v1.1/mRECIST.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Life expectancy ≥ 12 weeks.
6. Adequate organ and marrow function.
7. Tumor sample collection is required.

Exclusion Criteria:

1. Prior anti-cancer therapy within 2 weeks or at least 5 half-lives, whichever is longer, up to a maximum wash-out period of 21 days prior to the initiation of study drug administration.
2. Major surgery within 4 weeks of the first dose.
3. Radiotherapy with a limited field of radiation for palliation within 1 week prior to the first dose, with the exception as defined.
4. Patients currently receiving medications or herbal supplements known to be strong inhibitors or inducers of CYP3A4.
5. Patients currently receiving acid-reducing agents and are unable to stop use at least 2 weeks prior to the first dose.
6. Any known active central nervous system metastases and/or carcinomatous meningitis. Active infection including hepatitis B, hepatitis C, and HIV.
7. Any other clinically significant comorbidities, such as uncontrolled pulmonary disease, active infection, uncontrolled pericardial effusion, uncontrolled pleural effusion, or any other conditions, which in the judgment of Investigator, could compromise compliance with the protocol, interfere with the interpretation of study results, or predispose the patient to safety risks.
8. Any evidence of severe or uncontrolled systemic diseases which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.