Study of XL102 as Single-Agent and Combination Therapy in Subjects With Solid Tumors (QUARTZ-101)

NCT04726332 | Terminated Phase 1 FDA Drug

• 1 other identifier: XL102-101
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 5

Brief Summary

This is a Phase 1, open-label, dose-escalation and expansion study evaluating the safety, tolerability, PK, antitumor activity, and effect on biomarkers of XL102 administered orally alone and in multiple combination regimens to subjects with advanced solid tumors.

Conditions

Neoplasm Malignant; Epithelial Ovarian Cancer; Triple Negative Breast Cancer; Hormone Receptor Positive Breast Carcinoma; Metastatic Castration-resistant Prostate Cancer

Keywords

cdk7 inhibitor

Outcome Measures

Primary Outcomes (2)

• Dose-Escalation Stage: MTD/recommended dose for XL102

  To determine the MTD and/or RD for further evaluation of XL102 when administered orally alone and in combination therapy in subjects with advanced solid tumors

  Approximately 18 months

• Cohort-Expansion Stage: Objective Response Rate (ORR)

  To evaluate preliminary efficacy of XL102 when administered alone and in combination therapy by estimating the ORR as assessed by the Investigator per RECIST 1.1

  Approximately 12 months

Secondary Outcomes (8)

• Safety of XL102 as evaluated by Incidence and Severity of Adverse Events (AEs)

  Approximately 30 months

• Tolerability of XL102 as evaluated by Study Treatment Exposure, Dose Intensity and Modifications, and Study Treatment Discontinuation due to AE

  Approximately 30 months

• Dose-Escalation Stage: Drug-Drug Interactions

  Approximately 18 months

• Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax)

  Approximately 18 months

• Dose-Escalation Stage: Maximum Plasma Concentration (Cmax)

  Approximately 18 months

Study Arms (6)

XL102 Single-Agent Dose-Escalation Cohorts

EXPERIMENTAL

Subjects will be separated into three separate groups of cohorts. Formulation A consists of: Fasted, with approximately 9 cohorts (A-FC) starting at 20 mg (qd and/or bid) of XL102, Food-Effect Dose-Escalation at 40 mg qd of XL102, with approximately 3 cohorts (A-FE) and Non-Fasted, with approximately 6 cohorts (A-NF). Formulation B consists of additional cohorts: Fasted (A-FCFB) starting at 40 mg (qd and/or bid) of XL102 and Non-Fasted (A-NFCFB). The dose of the remaining A-FE cohorts will be determined by the Cohort Review Committee (CRC) as well as that of the A-NF, and A-NFCFB cohorts.

Drug: XL102

XL102 Single-Agent Expansion Cohorts

EXPERIMENTAL

The Maximum Tolerated Dose (MTD) or recommended dose from the dose-escalation stage may be further explored in subjects with triple-negative breast cancer (TNBC) (Cohort D), epithelial ovarian cancer (EOC) (Cohort E), hormone receptor-positive breast cancer (HR+ BC) (Cohort F), and metastatic castration-resistant prostate cancer (mCRPC) (Cohort G).

Drug: XL102

XL102 + Fulvestrant Dose-Escalation Cohorts

EXPERIMENTAL

Subjects with HR+ BC (Cohort B) will accrue in cohorts of 3-12 subjects in a modified i3+3 design.

Drug: XL102; Drug: Fulvestrant

XL102 + Abiraterone/Prednisone Dose-Escalation Cohorts

EXPERIMENTAL

Subjects with mCRPC (Cohort C) will accrue in cohorts of 3-12 subjects in a modified i3+3 design.

Drug: XL102; Drug: Abiraterone; Drug: Prednisone

XL102 + Fulvestrant Expansion Cohorts

EXPERIMENTAL

The MTD or recommended dose from the dose-escalation stage may be further explored in subjects with HR+ BC (Cohort H).

Drug: XL102; Drug: Fulvestrant

XL102 + Abiraterone/Prednisone Expansion Cohorts

EXPERIMENTAL

The MTD or recommended dose from the dose-escalation stage may be further explored in subjects with mCRPC (Cohort I).

Drug: XL102; Drug: Abiraterone; Drug: Prednisone

Interventions

XL102 DRUG

oral doses of XL102

XL102 + Abiraterone/Prednisone Dose-Escalation Cohorts; XL102 + Abiraterone/Prednisone Expansion Cohorts; XL102 + Fulvestrant Dose-Escalation Cohorts; XL102 + Fulvestrant Expansion Cohorts; XL102 Single-Agent Dose-Escalation Cohorts; XL102 Single-Agent Expansion Cohorts

Fulvestrant DRUG

fulvestrant 500 mg administered as an intramuscular (IM) injection every 2 weeks for the first 3 doses and then every 4 weeks.

XL102 + Fulvestrant Dose-Escalation Cohorts; XL102 + Fulvestrant Expansion Cohorts

Abiraterone DRUG

abiraterone 1000 mg administered orally once daily.

XL102 + Abiraterone/Prednisone Dose-Escalation Cohorts; XL102 + Abiraterone/Prednisone Expansion Cohorts

Prednisone DRUG

prednisone 5 mg administered orally twice daily.

XL102 + Abiraterone/Prednisone Dose-Escalation Cohorts; XL102 + Abiraterone/Prednisone Expansion Cohorts

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cytologically or histologically and radiologically confirmed solid tumor that is inoperable, locally advanced, metastatic, or recurrent.
• Dose-Escalation Stage Cohort A (Solid Tumors): The subject has a solid tumor that is unresectable or metastatic and for which life-prolonging measures do not exist or available therapies are intolerable or no longer effective.
• Dose-Escalation Stage Cohort B and Cohort-Expansion Stage Cohorts F and H (Hormone Receptor-Positive Breast Cancer): Subjects with breast cancer that is hormone receptor-positive (estrogen receptor positive \[ER+\] and/or progesterone receptor positive \[PR+\]) and negative for human epidermal growth factor receptor 2 (HER-2 negative \[HER-2-\]) and who have documented radiographic disease progression during or following their last systemic anticancer therapy for inoperable locally advanced or metastatic disease.
• Dose-Escalation Stage Cohort C and Cohort-Expansion Stage Cohorts G and I (Metastatic Castration-Resistant Prostate Cancer): Subjects with adenocarcinoma of the prostate. Note: Neuroendocrine differentiation and other histological features are permitted if adenocarcinoma is the primary histology.
• Cohort-Expansion Stage Cohort D (Triple Negative Breast Cancer): Subjects with breast cancer that is negative for HER-2, estrogen receptors, and progesterone receptors, and who have documented radiographic disease progression during or following their last systemic anticancer therapy for inoperable locally advanced or metastatic disease.
• Cohort-Expansion Stage Cohort E (Epithelial Ovarian Cancer): Subjects with epithelial ovarian cancer, including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC) who have platinum-resistant disease following treatment with a platinum-containing chemotherapy. Ovarian borderline epithelial tumors (low malignant potential) are excluded.
• Expansion Cohorts: Subjects must have measurable disease per RECIST 1.1 as determined by the Investigator.
• Tumor tissue material (archival or fresh tumor tissue \[if it can be safely obtained\]).
• Recovery to baseline or ≤ Grade 1 severity (Common Terminology Criteria for Adverse Events version 5 \[CTCAE v5\]) from AEs, unless AEs are clinically nonsignificant (eg, alopecia) or stable (eg, peripheral neuropathy).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• Adequate organ and marrow function.
• Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.

You may not qualify if:

• Receipt of XL102 or any other selective CDK7 inhibitor.
• Receipt of any cytotoxic chemotherapy therapy or anticancer antibody therapy within 21 days before first dose of study treatment.
• Receipt of any type of small molecule kinase inhibitor within 2 weeks before first dose of study treatment.
• Receipt of any anticancer hormonal therapy within 2 weeks or within 5 half-lives of the agent, whichever is shorter, before first dose of study treatment. HR+BC subjects enrolled in the Combination Cohorts B and H receiving fulvestrant prior to first dose of study treatment are allowed to continue with their fulvestrant treatment. Metastatic CRPC subjects enrolled in the Combination Cohorts C and I receiving abiraterone prior to first dose of study treatment are allowed to continue with their abiraterone treatment.
• Radiation therapy within 14 days before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain tumors and metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.
• Use of strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, and inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter.
• Use of a sensitive substrate of CYP3A4, CYP2B6, CYP2C8, CYP2C9, or BCRP transporter within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter. For subjects with mCRPC in receiving combination treatment with XL102 and abiraterone plus prednisone, use of a substrate of CYP2D6 with a narrow therapeutic index within 5 half-lives or 4 weeks prior to first dose of study treatment, whichever is shorter, is prohibited.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders: i. congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, torsades de pointes). ii. uncontrolled hypertension defined as sustained blood pressure \> 150 mmHg systolic or \>90 mm Hg diastolic despite optimal antihypertensive treatment. iii. stroke (including transient ischemic attack \[TIA\]), myocardial infarction, or other ischemic event or pulmonary embolism (PE) within 6 months before first dose. Note: Subjects with a diagnosis of deep vein thrombosis (DVT) within 6 months before first dose are allowed if managed adequately with anticoagulants and asymptomatic at the time of first dose.
• history of any lower gastrointestinal (GI) disorder (such as inflammatory bowel disease \[IBD\]) or any form of colitis (such as ulcerative colitis or Crohn's disease).
• history of upper gastrointestinal (GI) inflammatory disorder (eg, esophagitis, gastritis, or duodenitis), gastroparesis, symptomatic gastroesophageal reflux disease (GERD) despite medical therapy, or gastric or duodenal ulcers within 6 months.
• history of major surgical resection involving the stomach or small bowel or any other reason for a malabsorption syndrome.
• history of significant bleeding (eg, GI hemorrhage) within 12 weeks before first dose.
• active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, acute or chronic hepatitis B or C infection, or a known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease. Prophylactic use of antibiotics is allowed.

Sponsors & Collaborators

• Exelixis: lead

Study Sites (5)

Exelixis Clinical Site #4

Atlanta, Georgia, 30322, United States

Location

Exelixis Clinical Site #3

Boston, Massachusetts, 02215, United States

Location

Exelixis Clinical Site #2

Dallas, Texas, 75230, United States

Location

Exelixis Clinical Site #5

Houston, Texas, 77030, United States

Location

Exelixis Clinical Site #1

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Gaur T, Poddutoori R, Khare L, Bagal B, Rashmi S, Patkar N, Tembhare P, Pg S, Shetty D, Dutt A, Zhang Q, Konopleva M, Platzbeckar U, Gupta S, Samajdar S, Ramchandra M, Khattry N, Hasan SK. Novel covalent CDK7 inhibitor potently induces apoptosis in acute myeloid leukemia and synergizes with Venetoclax. J Exp Clin Cancer Res. 2023 Jul 29;42(1):186. doi: 10.1186/s13046-023-02750-w.

  PMID: 37507802 DERIVED

MeSH Terms

Conditions

Neoplasms; Carcinoma, Ovarian Epithelial; Triple Negative Breast Neoplasms

Interventions

Fulvestrant; abiraterone; Prednisone

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Breast Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnadienediols; Pregnadienes; Pregnanes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single-agent and combination therapy dose-escalation followed by cohort-expansion

Study Record Dates

• First Submitted: January 22, 2021
• First Posted: January 27, 2021
• Study Start: February 10, 2021
• Primary Completion: May 2, 2024
• Study Completion: May 2, 2024
• Last Updated: May 14, 2024

Record last verified: 2024-05

Locations

US (5)