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

• ClinicalTrials.gov Identifier: NCT04726332
• Recruitment Status: Active, not recruiting
• First Posted: January 27, 2021
• Last Update Posted: February 7, 2024
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Neoplasm Malignant; Epithelial Ovarian Cancer; Triple Negative Breast Cancer; Hormone Receptor Positive Breast Carcinoma; Metastatic Castration-resistant Prostate Cancer	Drug: XL102; Drug: Fulvestrant; Drug: Abiraterone; Drug: Prednisone	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 373 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: single-agent and combination therapy dose-escalation followed by cohort-expansion
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Dose Escalation and Expansion Study of the Safety and Pharmacokinetics of XL102 as Single-Agent and Combination Therapy in Subjects With Inoperable Locally Advanced or Metastatic Solid Tumors
• Actual Study Start Date: February 10, 2021
• Estimated Primary Completion Date: June 2024
• Estimated Study Completion Date: October 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: XL102 Single-Agent Dose-Escalation Cohorts; 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; oral doses of XL102
Experimental: XL102 Single-Agent Expansion Cohorts; 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; oral doses of XL102
Experimental: XL102 + Fulvestrant Dose-Escalation Cohorts; Subjects with HR+ BC (Cohort B) will accrue in cohorts of 3-12 subjects in a modified i3+3 design.	Drug: XL102; oral doses of XL102; Drug: Fulvestrant; fulvestrant 500 mg administered as an intramuscular (IM) injection every 2 weeks for the first 3 doses and then every 4 weeks.
Experimental: XL102 + Abiraterone/Prednisone Dose-Escalation Cohorts; Subjects with mCRPC (Cohort C) will accrue in cohorts of 3-12 subjects in a modified i3+3 design.	Drug: XL102; oral doses of XL102; Drug: Abiraterone; abiraterone 1000 mg administered orally once daily.; Drug: Prednisone; prednisone 5 mg administered orally twice daily.
Experimental: XL102 + Fulvestrant Expansion Cohorts; The MTD or recommended dose from the dose-escalation stage may be further explored in subjects with HR+ BC (Cohort H).	Drug: XL102; oral doses of XL102; Drug: Fulvestrant; fulvestrant 500 mg administered as an intramuscular (IM) injection every 2 weeks for the first 3 doses and then every 4 weeks.
Experimental: XL102 + Abiraterone/Prednisone Expansion Cohorts; The MTD or recommended dose from the dose-escalation stage may be further explored in subjects with mCRPC (Cohort I).	Drug: XL102; oral doses of XL102; Drug: Abiraterone; abiraterone 1000 mg administered orally once daily.; Drug: Prednisone; prednisone 5 mg administered orally twice daily.

Outcome Measures

Primary Outcome Measures :

1. Dose-Escalation Stage: MTD/recommended dose for XL102 [ Time Frame: Approximately 18 months ]
   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
2. Cohort-Expansion Stage: Objective Response Rate (ORR) [ Time Frame: Approximately 12 months ]
   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

Secondary Outcome Measures :

1. Safety of XL102 as evaluated by Incidence and Severity of Adverse Events (AEs) [ Time Frame: Approximately 30 months ]
   To evaluate the safety of XL102 when administered orally alone and in combination therapy through the evaluation of overall incidence of AEs, severity grade, relationship to study treatment, and laboratory tests.
2. Tolerability of XL102 as evaluated by Study Treatment Exposure, Dose Intensity and Modifications, and Study Treatment Discontinuation due to AE [ Time Frame: Approximately 30 months ]
   To evaluate the tolerability of XL102 when administered orally alone and in combination therapy through the evaluation of study treatment exposure, dose intensity, dose modifications, and study treatment discontinuation due to AE.
3. Dose-Escalation Stage: Drug-Drug Interactions [ Time Frame: Approximately 18 months ]
   To assess drug-drug interactions between XL102 and combination agents
4. Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Approximately 18 months ]
   To evaluate the Tmax of XL102 alone and in combination therapy
5. Dose-Escalation Stage: Maximum Plasma Concentration (Cmax) [ Time Frame: Approximately 18 months ]
   To evaluate the Cmax of XL102 alone and in combination therapy
6. Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24) [ Time Frame: Approximately 18 months ]
   To evaluate the AUC 0-24 of XL102 alone and in combination therapy
7. Dose-Escalation Stage: Terminal Half-Life [ Time Frame: Approximately 18 months ]
   To evaluate the terminal half-life of XL102 alone and in combination therapy
8. Dose-Escalation Stage: Apparent Clearance (CL/F) [ Time Frame: Approximately 18 months ]
   To evaluate the CL/F of XL102 alone and in combination therapy

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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:

  1. 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.
  2. 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).
  3. 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.
  4. history of major surgical resection involving the stomach or small bowel or any other reason for a malabsorption syndrome.
  5. history of significant bleeding (eg, GI hemorrhage) within 12 weeks before first dose.
  6. 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.
  7. History of COVID-19 unless the subject has clinically recovered from the infection: at least 10 days prior to first dose or sooner, if COVID-19 PCR negative.
  8. moderate to severe hepatic impairment (child-pugh B or C)
  9. requirement for hemodialysis or peritoneal dialysis
  10. history of solid organ, autologous or allogenic stem cell transplant
• Concomitant use of certain medications.
• Uncontrolled, significant intercurrent or recent illness.
• Major surgery within 4 week before first dose of treatment. Minor surgery within 7 days before first dose of treatment. Complete wound healing from surgery must have occurred before first dose of treatment.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG).
• History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.
• Inability to swallow oral study treatment formulation
• Previously identified allergy or hypersensitivity to study treatment formulation
• Pregnant or lactating females.
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.
• For subjects in Food-Effect Cohorts (A-FE) only: i. Known inability to tolerate high-fat meal provided on Day 1 ii. Allergy to meal components or dietary restrictions iii. Unable to fast for 4 hours predose and 2 hours post dose on Day 8

Contacts and Locations

Locations

United States, Georgia

Exelixis Clinical Site #4

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Exelixis Clinical Site #3

Boston, Massachusetts, United States, 02215

United States, Texas

Exelixis Clinical Site #2

Dallas, Texas, United States, 75230

Exelixis Clinical Site #5

Houston, Texas, United States, 77030

Exelixis Clinical Site #1

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Exelixis

More Information

• Responsible Party: Exelixis
• ClinicalTrials.gov Identifier: NCT04726332
• Other Study ID Numbers: XL102-101
• First Posted: January 27, 2021
• Last Update Posted: February 7, 2024
• Last Verified: February 2024

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Exelixis:

cdk7 inhibitor

Additional relevant MeSH terms:

Triple Negative Breast Neoplasms; Breast Neoplasms; Carcinoma, Ovarian Epithelial; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Diseases; Urogenital Diseases; Ovarian Neoplasms; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Neoplasms, Female; Endocrine System Diseases; Gonadal Disorders; Breast Diseases; Skin Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Prednisone; Fulvestrant; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs