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Lay Description

This study is an open-label, multi-center, dose-escalation, dose-expansion study in adult subjects with advanced solid tumors. The study will evaluate the safety, tolerability, PK, and preliminary anti-tumor efficacy of SM08502 administered orally (PO), once daily (QD), following a 5 days on 2 days off treatment schedule. Alternative dosing schedules may be explored in Part 1 if necessary. The recommended Part 2 dose and schedule for each combination will then be further evaluated in the Part 2 expansion. See below for further details regarding regimens in Parts 1 and 2.

Category

  • Cancers and Other Neoplasms
  • Solid Tumor
IRB Number
20210640HU
NCT Number
ct.gov registration not required
Open to Enrollment
Yes

Eligibility

Eligible Ages
18
Eligible Genders
All
Accepts Healthy Volunteers

Inclusion Criteria

Other Inclusion Criteria: Subjects with advanced solid tumors (as defined below):

    1. Part 1 – Subjects with advanced and/or metastatic solid tumors. Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. The tumor types include:
      • i. CRPC – Subjects with progressive disease in the setting of medical or surgical castration (i.e., castration-resistant prostate cancer) and:
      • (1) Evidence of disease progression by rising PSA (PSA on study entry at least 2 ng/ml if no measurable disease), progression by PSA requires rising PSA over a previous reference value by at least 2 measurements obtained ≥1 week apart, or
      • (2) Soft tissue/visceral progression per RECIST 1.1, or
      • (3) Evidence of disease progression by observation of ≥ 2 new bone lesions since the initiation of last systemic therapy.
      • (4) Must have been on prior therapy with a second-generation anti-hormonal therapy (e.g., enzalutamide, apalutamide, darolutamide, or abiraterone) for at least 3 months with evidence of progression based on PSA or imaging criteria above.

(5) Must have undergone bilateral orchiectomy (surgical castration) or be willing to continue GnRH analog or antagonist (medical castration).

(6) Serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.

            (7) Subjects who have received three or more prior lines of chemotherapy in any setting are             excluded, however, subjects who are not candidates for chemotherapy or refuse chemotherapy are eligible. Prior radium therapy is permitted.

(8) Must have metastatic disease documented by CT, MRI, bone scan, or PET scan.

      • NSCLC (adenocarcinoma subtype) – Subjects with no targetable mutations must have received a platinum-containing doublet chemotherapy regimen and a checkpoint inhibitor (either in combination or monotherapy, if indicated) and have progressed. Subjects with targetable mutations/alterations such as EGFR, ALK, or NTRK must have received prior targeted therapy and have progressed.
      • iii. CRC - Subjects must have received one prior line of standard chemotherapy such as FOLFOX +/- a VEGF-inhibitor and have progressed or are intolerant of oxaliplatin based regimens. In addition:
      • (1) All subjects must have received a minimum of 6 weeks of the first line regimen that included oxaliplatin and a fluoropyrimidine.
      • (2) Subjects who show tumor progression while on maintenance therapy with first line agents are eligible and this will be considered one line of therapy.
      • (3) Subjects who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was administered) will be required to receive fluoropyrimidine/oxaliplatin-based therapy with or without a VEGF inhibitor for metastatic disease.
      • (4) For subjects with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen.
      • (5) Subjects who received prior irinotecan, or who have tumors that are MSI high or harbor B-RAF or RAS mutations will be excluded
    • 2 – Subjects with advanced and/or metastatic solid tumors. Histologic or cytologic confirmation of malignancy must have been obtained at diagnosis. The tumor types include:
      • i. CRPC – Subjects with progressive disease in the setting of medical or surgical castration (i.e., castration- resistant prostate cancer) and:
      • (1) Evidence of disease progression by rising PSA (PSA on study entry at least 2 ng/ml if no measurable disease), progression by PSA requires rising PSA over a previous reference value by at least 2 measurements obtained ≥1 week apart, or
      • (2) Soft tissue/visceral progression per RECIST 1.1, or

(3) Evidence of disease progression by observation of ≥2 new bone lesions since the initiation of last systemic therapy.

(4) Must have been on prior therapy with abiraterone for at least 3 months with evidence of progression based on PSA or imaging criteria above.

(5) Must have undergone bilateral orchiectomy (surgical castration) or be willing to continue GnRH analog or antagonist (medical castration).

(6) Serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.

(7) Subjects who have received three or more prior lines of chemotherapy in any setting are excluded, however, subjects who are not candidates for chemotherapy or refuse chemotherapy are eligible. Prior radium therapy is permitted.

(8) Must have metastatic disease documented by CT, MRI, bone scan, or PET scan.

      • ii. NSCLC (adenocarcinoma subtype) – Subjects with no targetable mutations must have received a platinum-containing doublet chemotherapy regimen and a checkpoint inhibitor (either in combination or monotherapy, if indicated) and have progressed. Subjects with targetable mutations/alterations such as EGFR, ALK, NTRK must have received prior targeted therapy and have progressed.
      • CRC - Subjects must have received one prior line of standard chemotherapy such as FOLFOX +/- either a VEGF-inhibitor or EGFR inhibitor (if indicated) and have progressed or are intolerant of oxaliplatin based regimens. In addition:
      • (1) All subjects must have received a minimum of 6 weeks of the first line regimen that included oxaliplatin and a fluoropyrimidine.
      • (2) Subjects who show tumor progression while on maintenance therapy with first line agents are eligible and this will be considered one line of therapy.
      • (3) Subjects who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was administered) will be required to receive fluoropyrimidine/oxaliplatin-based therapy with or without VEGF or EGFR inhibitor for metastatic disease.
      • (4) For subjects with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen.
      • (5) Subjects who received prior irinotecan, or who have tumors that are MSI high or harbor B-RAF mutations will be excluded.

Measurable or evaluable disease per RECIST 1.1 (Part 1). For Part 2, at least one measurable lesion per RECIST 1.1 that has not been previously irradiated. In CRPC subjects (Parts 1 and 2) without measurable disease per RECIST 1.1, a PSA that is concordant with clinical disease progression (rising) is eligible. A PSA value of 2 ng/ml or greater is required for study entry for those without measurable disease.

4. Subjects must have archived tumor specimens available for analysis (as specified in Section 8.6.2). Otherwise, a fresh tumor biopsy will be required at study entry. For prostate cancer subjects with bone only disease and fewer than the required archived slides, these subjects may be permitted to enter the study without a fresh biopsy but only after approval by the Medical Monitor.

Subjects must have recovered (i.e., Grade 1 [or better] based on CTCAE v5.0) from all toxicity associated with previous chemotherapy, targeted therapy, experimental therapy, biological therapy, immuno-oncology therapy, surgery, radiotherapy, or other locoregional therapy. Exceptions: Subjects may enter with continuing alopecia regardless of any CTCAE grade or with Grade 2 or better neuropathy; and subjects with immunotherapy-related toxicities (e.g., hypothyroidism or adrenal insufficiency) are eligible provided these are well controlled with hormone replacement for example, or the toxicities are stable and not expected to provide increased risk for study participation. The following intervals must elapse between end of last treatment and receiving the first dose of SM08502:

    1. Chemotherapy: 3 weeks
    2. Mitomycin C or a nitrosourea: 6 weeks
    3. Radiotherapy: 3 weeks
    4. Major surgery: 6 weeks
    5. Targeted therapy, including monoclonal antibodies and immuno-oncology therapies: 4 weeks or 5 half-lives, whichever is shortest
    6. Anti-hormonal therapy: 3 weeks for enzalutamide, apalutamide, or darolutamide. ADT is permitted for subjects with prostate cancer. For subjects progressing on abiraterone and switching directly to abiraterone combined with SM08502, no abiraterone washout period is required.
    7. Experimental therapy: 4 weeks or 5 half-lives, whichever is shortest
    8. Radium-223 therapy: 4 weeks
    9. Other locoregional therapy [e.g., radiofrequency ablation (RFA), TACE (transarterial chemoembolization), TARE (transarterial radioembolization), DEB-TACE (drug eluting bead transarterial chemoembolization)]: 6 weeks

Subjects must meet the following laboratory criteria at Screening for study entry:

    1. Hepatic function: serum total bilirubin ≤ 1.5x upper limit of normal (ULN), AST/ALT ≤ 2.5x ULN. For subjects with Gilbert’s syndrome, serum total bilirubin ≤ 3x ULN.
    2. Renal function: measured or calculated creatinine clearance via Cockcroft-Gault formula >35 mL/min
    3. Hematology: absolute neutrophil counts ≥ 1500/mm3, platelet counts ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL. Red blood cell (RBC) transfusion within 2 weeks prior to study entry is not permitted.
    4. Coagulation: prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5x ULN

Subjects with values within 10% of these limits deemed not clinically significant by the Investigator may be entered with the approval of the Medical Monitor.

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

8. Life expectancy > 3 months

9. Subjects must have no uncontrolled intercurrent illness

10. Subjects must have the ability to swallow and retain oral medication

11. Subjects must be willing to avoid extensive sun exposure, phototherapy, and use of a tanning salon during trial participation.

12. Subjects must be willing to sign and provide informed consent and be capable of giving informed consent in accordance with the Institutional Review Board (IRB) / Ethics Committee (EC) policy

13. Willingness to comply with all scheduled study visits, laboratory tests, contraception requirements, and other study procedures

14. Study cohort(s) is open for enrollment




Exclusion Criteria

Women who are pregnant or lactating

2. Women of childbearing potential (WOCBP) must agree to follow the contraceptive guidelines as outlined in protocol Section 5.3.1

3. Men of reproductive potential must agree to follow the contraceptive guidelines as outlined in protocol Section 5.3.1

4. Subjects with a QTc (Fridericia’s) prolongation > CTCAE v5.0 Grade 1 (>480 msec) at Screening

5. Subjects with clinically significant ventricular tachycardia (VT), atrial fibrillation (AF), ventricular fibrillation (VF), second- or third-degree heart block

6. Subjects with myocardial infarction (MI) within 1 year, Class II-IV congestive heart failure (CHF) per New York Heart Association (NYHA) classification, or clinically significant coronary artery disease (CAD)

7. Subjects currently using or anticipating the need for food or drugs known to strongly inhibit or induce CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, or rifampin; refer to Section 10.3), within 10 days prior to Day 1

8. Subjects with active infection (e.g., requiring antibiotic therapy); subjects with minor infections such as urinary tract infections must have completed therapy prior to Day 1 (these cases should be discussed with the Medical Monitor)

Organ transplant recipients

10. Subjects with untreated, progressing, or known symptomatic brain metastasis. Asymptomatic subjects whose brain metastasis have been adequately treated and have remained stable for 1 month (based on screening MRI of the brain compared to prior evaluations) and have discontinued corticosteroid treatment and are on a stable dose of anti-convulsant for 1 month (if required) are eligible.

Subjects with known osteoporosis (T-score of ≤ −2.5 at the spine or hip on DXA or individuals who have experienced a bone fracture due to osteoporosis)

12. Subjects with a second malignancy unless adequately treated with no recurrence for 3 years. Subjects with a history of previous or recent adequately treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of any source are eligible.

13. Subjects with known hypersensitivity to any excipients in the study drug formulation

14. Subjects with active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of SM08502 per Investigator’s opinion

15. Subjects with known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection

16. Subjects considered by the Investigator to be unsuitable for the study for any other reason

17. Subjects with pathologic retinal abnormalities, including subjects with diabetic retinopathy, macular degeneration, or other known forms of retinal degenerative disease

18. Subjects with chronic liver disease or dysfunction and a Child-Pugh score of B or C

19. Subjects who are immediate family members (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at any investigative site, or are directly affiliated with the study at any investigative site

20. Subjects employed by the Sponsor, or any of its affiliates or development partners (that is, an employee, temporary contract worker, or designee) responsible for the conduct of the study, or who are immediate family members (spouse, parent, child, or sibling; biological or legally adopted) of said employees responsible for the conduct of the study

Study Design

Arm Groups

Study Contact


Regulatory Point of Contact
Frances Crawford
(210) 450-5037
crawfordf1@uthscsa.edu

Regulatory Point of Contact
Sonia Creighton
(210) 450-1366
creighton@uthscsa.edu

Regulatory Point of Contact
Myrna Montenegro
(210) 450-5954
montenegro@uthscsa.edu

Regulatory Point of Contact
Mailbox Ctrc Regulatory Affairs
regaffapp@uthscsa.edu

Regulatory Point of Contact
Kathleen Rodriguez
(210) 450-1365
rodriguezk3@uthscsa.edu

Regulatory Point of Contact
Benjamin Schleif
(210) 450-1366
schleifb@uthscsa.edu

Regulatory Point of Contact
Morgan Seekatz
(210) 450-1133
seekatz@uthscsa.edu

Principal Investigator
Daruka Mahadevan