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ASTX 1512   |   12-974
A Study of HSP90 Inhibitor AT13387 Alone and in Combination with Crizotinib in the Treatment of Non-small Cell Lung Cancer (NSCLC)

Main Campus
Crizotinib (Xalkori)

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Primary Objectives

Part A

  • To establish the safety and MTD of AT13387 when administered in combination with crizotinib.

Part B

  • To compare the PFS between the administration of single-agent crizotinib and the combination of crizotinib + AT13387 in subjects with NSCLC who will be treated with crizotinib or who were treated with crizotinib and have not yet progressed.

Part C

  • To assess the efficacy (Objective Response Rate [ORR] = complete response [CR] + partial response [PR]) of single-agent AT13387 and to assess the efficacy of the addition of AT13387 to crizotinib in subjects who progressed on treatment with crizotinib.
Secondary Objectives

Part A

  • To assess the pharmacodynamic depletion of relevant client proteins after treatment with AT13387;
  • To assess the antitumor activity of the crizotinib + AT13387 combination (ORR [CR + PR]), PFS, and overall survival (OS); and
  • To assess the pharmacokinetic interaction between AT13387 and crizotinib.

Part B

  • To assess the safety of AT13387 in combination with crizotinib in subjects with NSCLC;
  • To compare the OS between crizotinib and crizotinib + AT13387
  • To compare ORR between crizotinib and crizotinib + AT13387 for subjects with measurable disease at baseline; and
  • To assess ORR (CR + PR) in crizotinib patients who crossover to crizotinib + AT13387 and have measurable disease at the time of crossover.

Part C

  • To assess the safety of AT13387 alone and in combination with crizotinib in subjects who progressed on crizotinib treatment and
  • To assess and compare the PFS and OS of AT13387 administered alone or in combination with crizotinib in subjects who progressed on crizotinib treatment.
Exploratory Objective
  • To identify potential biomarkers for predicting antitumor activity for AT13387 alone and in combination with crizotinib.

Inclusion Criteria
  1. Men or women ≥18 years of age;
  2. Have a histologically or cytologically confirmed NSCLC that is ALK+ or has other mutations or rearrangements that are potentially sensitive to crizotinib and have been receiving or have received crizotinib, regardless of other prior anticancer therapies including other ALK inhibitors;
  3. Presence of disease as described in Inclusion Criterion 4 for the different parts of the study;
    • In Part A, subjects must have received and been tolerant to at least 8 weeks of crizotinib 250 mg BID in the past regardless of when it was taken and the number of other intervening anticancer therapies, including other ALK inhibitors that may have been taken since the last dose of crizotinib. In part A, subjects with any response category may be enrolled as long as there is a chance of potential added benefit from continuing crizotinib in combination with AT13387 even if there is evidence of disease progression while on crizotinib monotherapy;
    • In Part B, subjects who are currently receiving and tolerating crizotinib and have not progressed by RECIST 1.1. or have not yet started but are eligible to receive crizotinib; and
    • In Part C, only subjects who are progressing or had previously progressed based on RECIST 1.1 at any time on crizotinib (including those who went on to receive other therapy including other ALK inhibitors before enrollment) will be enrolled;
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 for Part A and ≤2 for Parts B and C;
  5. Have adequate bone marrow function defined as absolute neutrophil count >1.5 K/μL and platelet count >75 K/μL;
  6. Have adequate hepatic function, defined as bilirubin ≤1.5 x ULN and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (ALT and AST ≤5 x ULN, if liver metastases are present);
  7. Have adequate renal function, defined as serum creatinine ≤1.25 x ULN or estimated creatinine clearance >50mL/min;
  8. Have adequate cardiac function and normal cardiac repolarization defined as:
    • QTc ≤480 msec and
    • LVEF ≥50% or within institutional limits of normal by echocardiogram (ECHO) or multigated acquisition (MUGA) scan;
  9. Female subjects who are either:
    • Not pregnant (must have a negative pregnancy test at screening) or breastfeeding and not planning to become pregnant during the study;
    • Not of childbearing potential, defined as one who has been postmenopausal (no menses AND either age ≥65 years or follicle-stimulating hormone levels in the menopausal range) for at least 1 year, has been surgically sterilized by bilateral oophorectomy, or has had a hysterectomy;
  10. Subjects and their female partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months following the last dose of the study drug. Effective contraception includes methods such as oral contraceptives, doublebarrier method (condom plus spermicide or diaphragm), or abstaining from sexual intercourse; and
  11. Able and willing to provide written informed consent and to comply with the protocol and study procedures.

Exclusion Criteria
  1. Prior anti-cancer treatment with any HSP90 inhibitor;
  2. Have received chemotherapy, radiation therapy, or other anticancer treatment other than crizotinib within 3 weeks prior to the first dose of study drug unless the washout period of those treatments has clearly exceeded 5 pharmacokinetic half-lives and any associated clinically significant toxicity has resolved to ≤Grade 1;
  3. Subjects with a prior malignancy other than adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, low-grade cervical cancer, nonmetastatic prostate cancer with normal PSA, or other cancer from which the subject has been disease-free for at least 3 years;
  4. Known symptomatic brain or central nervous system metastases (Note: Patients with asymptomatic brain metastases or any brain metastases that have been stable for ≥4 weeks may be included);
  5. Documented QTc prolongation >480 msec related to crizotinib on multiple measurements in ECGs during prior treatment with crizotinib;
  6. ≥Grade 2 bilirubin or transaminases on multiple measurements related to crizotinib while receiving crizotinib;
  7. ≥Grade 2 visual disturbances related to crizotinib while receiving crizotinib treatment;
  8. Congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or clinically significant uncorrected electrolyte imbalance, particularly hypokalemia <3 mmol/L unless corrected;
  9. Presence of a serious illness, active infection, medical condition, organ system dysfunction, or other factors which, in the Investigator's opinion, could compromise the subject's safety, negatively interact with AT13387, or compromise the integrity of the study outcomes;
  10. Hypersensitivity to AT13387 or other components of the drug product;
  11. For Part C, subjects who discontinued treatment with crizotinib due to a crizotinib-related toxicity;
  12. Treatment with any investigational drug within 3 weeks prior to the first dose of study drug or at least until any clinically significant residual toxicity from the investigational agent has resolved to ≤Grade 1 and at least 5 pharmacokinetic half-lives (if known) have elapsed;
  13. Subjects who are a poor medical risk because of other systemic diseases or active uncontrolled infections; or
  14. Known history of human immunodeficiency virus or seropositive test for hepatitis C virus or hepatitis B virus.

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