Patient case: 70-year-old male with gastrointestinal stromal tumor; genetic feature: KIT (V654A)

Clinical trial: Study of SNX-5422 in TP53 Null Cancers

Summary: SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Initial in vitro evidence supports that SNX-5422 may be active against TP53 null tumors irrespective of tumor type .

Detailed description: The tumor suppressor gene TP53 codes for a central regulator of the DNA-damage-response pathway, and its activation leads to cell-cycle arrest and DNA repair, apoptosis, or senescence through both transcription-dependent and transcriptional-independent activities. Somatic TP53 gene alterations are frequent in most human cancers.
  SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Inhibitors of the chaperone protein Hsp90 are of current interest because of the central role that Hsp90 plays in the maturation and maintenance of numerous proteins that are critical for tumor cell viability and growth.
  SNX-2112 retains activity in cell lines with loss of the TP53 gene from one of the alleles. SNX-2112 displays good activity in cell lines with TP53 null/TP53 wild type (e.g., MEC-1 [chronic lymphocytic leukemia]) and TP53 null/TP53 mutation (e.g., EBC-1, NCI-H520 [all NSCLC - squamous cell carcinoma]). Even in the most extreme case in which TP53 is lost from both alleles, i.e., the cancer cell is totally devoid of the TP53 gene (e.g., H1299, KATO III, HL-60, SK-MES-1), SNX-2112 retains activity
  It appears that SNX-2112 could be active against both hematological and solid tumors with a TP53 null status.

Eligibility: Inclusion Criteria:
  -  Confirmed solid or hematological TP53 null type cancer.
  -  No more than 4 prior lines of systemic anti-cancer therapy.
  -  Males or non-pregnant, non-breastfeeding females 18 years-of-age or older.
  -  Karnofsky performance score 60
  -  Life expectancy of at least 3 months.
  -  Adequate baseline laboratory assessments
  -  Recovered from toxicities of previous anticancer therapy to CTCAE Grade ≤ 1 with the exception of alopecia.
  Exclusion Criteria:
  -  Treatment with an investigational agent within 30 days prior to the first dose of SNX‑5422 or planning to receive an investigational agent during the study.
  -  Treatment with other anticancer drugs within 28 days or 5 half-lives of anticancer therapy (whichever is shorter) is prohibited from 30 days prior to the first dose of SNX-5422 and throughout the study.
  -  Radiation treatment within 2 weeks.
  -  The need for treatment with medications with clinically relevant metabolism by the cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of SNX-5422 (Appendix B).
  -  Appropriately corrected screening ECG QTc interval 470 msec for females, 450 msec for males.
  -  Currently receiving medications known to cause QT prolongation AND corrected QTc of 450 msec for females, 430 msec for males.
  -  Patients with chronic diarrhea of grade 2 or greater despite maximal medical management.
  -  Gastrointestinal diseases or conditions that could affect drug absorption, including gastric bypass.
  -  Gastrointestinal diseases that could alter the assessment of safety, including irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic coloproctitis.
  -  History of documented adrenal dysfunction not due to malignancy.
  -  Seropositive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV).
  -  History of chronic liver disease.
  -  Active hepatitis A or B.
  -  Current alcohol dependence or drug abuse.
  -  Clinically significant glaucoma, retinitis pigmentosa, or macular degeneration.
  -  Other serious concurrent illness or medical condition.

Relevance to patient case: not relevant