Phase 1b of Lurbinectedin in Combination With Weekly Paclitaxel and Bevacizumab in Platinum-resistant Ovarian Cancer

• ClinicalTrials.gov Identifier: NCT05636111
• Recruitment Status: Not yet recruiting
• First Posted: December 5, 2022
• Last Update Posted: June 5, 2023
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: Jazz Pharmaceuticals
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

To learn if adding lurbinectedin to the combination of paclitaxel and bevacizumab can help to control advanced cancer.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer	Drug: Paclitaxel; Drug: Bevacizumab; Drug: Lurbinectedin	Phase 1

Detailed Description:

Primary Objectives:

• To identify dose-limiting toxicities (DLTs) and recommended phase 2 dose (RP2D) of the combination of paclitaxel/bevacizumab/lurbinectedin in women with platinum resistant ovarian cancer.
• To assess macrophage counts by image cytometry in women with platinum resistant ovarian cancer treated with weekly paclitaxel/bevacizumab/lurbinectedin.

Secondary Objectives:

• To assess objective response (OR) and duration of response (DOR).
• To assess clinical benefit rate (CBR), defined as proportion of patients with OR or stable disease (SD) > 4 months.
• To estimate progression free survival (PFS) and overall survival (OS) for at least 12 months

Exploratory Objectives:

--To assess differential effects from baseline, within and between patient treatment cohorts, on macrophage and hypoxia markers, CSF1/R and MHCII, plasma biomarker (VEGF, VEGFR, IL6, IL8, FGF, PDGFAA), tumor and macrophage-derived exosomes, resident macrophage populations in tissue pre-enrollment and after induction bevacizumab (CD11b +CD68, CD11b +CD14/CD15/CD33, CD11b +CD11c, MHCII, CD168+, CD4/CD8, NK, Treg) by multicolor tissue cytometry, as well as serial changes in vivo imaging such as tumor size, macrophage-specific imaging, ADC for cellularity, and DCE for vasculature.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1b of Lurbinectedin in Combination With Weekly Paclitaxel and Bevacizumab in Platinum-resistant Ovarian Cancer
• Estimated Study Start Date: May 31, 2023
• Estimated Primary Completion Date: July 31, 2024
• Estimated Study Completion Date: July 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Escalation and Dose Expansion; Pariticipants will be assigned to a dose level of combined paclitaxel, bevacizumab, and lurbinectedin	Drug: Paclitaxel; Given by (IV) vein; Other Name: Taxol; Drug: Bevacizumab; Given by (IV) vein; Other Names: Avastin™; Anti-VEGF monoclonal antibody; rhuMAb-VEGF; Drug: Lurbinectedin; Given by (IV) vein

Outcome Measures

Primary Outcome Measures :

1. Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 [ Time Frame: through study completion; an average of 1 year. ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

Inclusion criteria will be assessed within 28 days of starting study treatment:

1. Ability to provide signed informed consent in accordance with federal, local, and institutional guidelines.
2. Age ≥ 18 years at time of study entry
3. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

4. Histologically confirmed and documented ovarian, fallopian tube or peritoneal carcinoma: both platinum refractory* and platinum resistant** patients. Anti-VEGF targeted therapy (e.g. bevacizumab, VEGF TKI's) is allowed as part of initial therapy and/or maintenance. No prior bevacizumab for treatment of platinum-resistant/platinum-refractory disease.

   Platinum refractory is defined as progression during platinum-containing therapy or within 4 weeks of last dose.

   ** Platinum resistant is defined as relapse-free interval 1-6 months of a platinum-containing therapy

5. Prior Therapy: Unlimited prior systemic therapies are allowed.
6. ECOG performance status of 0-1 (Appendix A)

7. Adequate normal organ and marrow function as defined below.

   1. Hemoglobin ≥9.0 g/dL.
   2. Absolute neutrophil count (ANC) > 1500/mm3.
   3. Platelet count ≥100 x 109/L
   4. Serum bilirubin ≤1.5 x ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
   5. AST (SGOT)/ALT (SGPT) ≤2.5 x ULN unless liver metastases are present, in which case it must be ≤5x ULN.
   6. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

   Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

8. Evidence of post-menopausal status or negative urine or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

   1. Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
   2. Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.
   3. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

Exclusion Criteria:

Exclusion criteria will be assessed within 28 days of starting study treatment. Patients meeting any of the following exclusion criteria are not eligible to enroll in this study.

1. Patients who have received anti-VEGF targeted therapy (alone or in combination with chemotherapy or other biological agents) for platinum-resistant/platinum-refractory recurrent disease.
2. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤2 weeks prior to cycle 1 day 1.
3. Use of an anti-cancer treatment drug or investigational drug during the last 28 days or 5 half-lives (whichever is shorter) prior to cycle 1 day 1. A minimum of 10 days between termination of prior treatment and administration of study treatment is required.
4. Patients with known or suspected conditions likely to increase gastrointestinal toxicity, such as inflammatory bowel disease, bowel obstruction, history of bowel obstruction, or overt bowel involvement by tumor.
5. Patients who are pregnant or lactating.
6. Major surgery </= 28 days prior to cycle 1 day 1.

7. Unstable cardiovascular function:

   1. ECG abnormalities requiring treatment, or
   2. congestive heart failure (CHF) of NYHA Class ≥3, or
   3. myocardial infarction (MI) within 3 months.
8. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study.
9. Any known history or evidence of hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); Known to be HIV seropositive
10. Any underlying condition that would significantly interfere with the absorption of an oral medication.
11. Grade >2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1).
12. Serious psychiatric or medical conditions that could interfere with treatment;
13. Participation in an investigational anti-cancer study within 3 weeks prior to Cycle 1 Day 1
14. Concurrent therapy with approved or investigational anticancer therapeutic other than steroids.
15. Patients with coagulation problems and active bleeding within 4 weeks prior to C1D1 (peptic ulcer, epistaxis, spontaneous bleeding)
16. Patients with symptomatic brain lesions
17. For women who are not postmenopausal (<12 months of non therapy-induced amenorrhea, with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or use two adequate non hormonal methods of contraception, including at least one method with a failure rate of <1% per year, during the treatment period and for at least three months after the last dose of study drug.

Examples of non-hormonal contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• History of hemoptysis (1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment for any tumor type.
• Non-healing wound, ulcer or bone fracture.
• Known hypersensitivity to lurbinectedin, paclitaxel, bevacizumab or excipients.

Contacts and Locations

Contacts

Contact: Shannon Westin, MD; 713-794-4314; swestin@mdanderson.org

Locations

United States, Texas

M D Anderson Cancer Center

Houston, Texas, United States, 77030

Contact: Shannon Westin, MD 713-794-4314 swestin@mdanderson.org

Principal Investigator: Shannon Westin, MD

Sponsors and Collaborators

M.D. Anderson Cancer Center

Jazz Pharmaceuticals

Investigators

• Principal Investigator: Shannon Westin, MD; M.D. Anderson Cancer Center

More Information

Additional Information:

M D Anderson Cancer Center 

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT05636111
• Other Study ID Numbers: 2022-0231; NCI-2022-10037 ( Other Identifier: NCI-CTRP Clinical Trials Registry )
• First Posted: December 5, 2022
• Last Update Posted: June 5, 2023
• Last Verified: June 2023

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

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; 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; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Paclitaxel; Bevacizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents