Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. We performed a safety lead-in followed by expansion in endometrial...
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| Veröffentlicht in: | Clinical cancer research Jg. 27; H. 23; S. 6354 |
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| Abstract | On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.
We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.
A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (
= 6); therefore, DL1 was reexplored (
= 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.
The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit. |
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| AbstractList | On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.
We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.
A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (
= 6); therefore, DL1 was reexplored (
= 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.
The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit. On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.PURPOSEOn the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.PATIENTS AND METHODSWe performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.RESULTSA total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.CONCLUSIONSThe combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit. |
| Author | Chelariu-Raicu, Anca Soliman, Pamela T Kim, Tae-Beom Frumovitz, Michael Labrie, Marilyne Blucher, Aurora Marszalek, Joseph R Yuan, Ying Liu, Jinsong Meyer, Larissa A Sood, Anil K Ma, XiaoYan Lu, Karen H Lee, Sanghoon Fang, Yong Schmeler, Katheleen M Chen, Tsun Hsuan Kabil, Nashwa Jazaeri, Amir Vellano, Christopher P Feng, Ningping Sun, Charlotte C Coleman, Robert L Westin, Shannon N Creason, Allison Litton, Jennifer K Murthy, Rashmi Fellman, Bryan Mills, Gordon B |
| Author_xml | – sequence: 1 givenname: Shannon N orcidid: 0000-0002-1922-0156 surname: Westin fullname: Westin, Shannon N email: swestin@mdanderson.org organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas. swestin@mdanderson.org – sequence: 2 givenname: Marilyne surname: Labrie fullname: Labrie, Marilyne organization: Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon – sequence: 3 givenname: Jennifer K surname: Litton fullname: Litton, Jennifer K organization: Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 4 givenname: Aurora orcidid: 0000-0001-6460-010X surname: Blucher fullname: Blucher, Aurora organization: Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon – sequence: 5 givenname: Yong surname: Fang fullname: Fang, Yong organization: Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon – sequence: 6 givenname: Christopher P surname: Vellano fullname: Vellano, Christopher P organization: TRACTION, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 7 givenname: Joseph R surname: Marszalek fullname: Marszalek, Joseph R organization: TRACTION, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 8 givenname: Ningping orcidid: 0000-0003-1917-9648 surname: Feng fullname: Feng, Ningping organization: TRACTION, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 9 givenname: XiaoYan surname: Ma fullname: Ma, XiaoYan organization: TRACTION, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 10 givenname: Allison orcidid: 0000-0001-5724-1276 surname: Creason fullname: Creason, Allison organization: Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon – sequence: 11 givenname: Bryan surname: Fellman fullname: Fellman, Bryan organization: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 12 givenname: Ying surname: Yuan fullname: Yuan, Ying organization: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 13 givenname: Sanghoon surname: Lee fullname: Lee, Sanghoon organization: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 14 givenname: Tae-Beom surname: Kim fullname: Kim, Tae-Beom organization: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 15 givenname: Jinsong surname: Liu fullname: Liu, Jinsong organization: Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 16 givenname: Anca orcidid: 0000-0003-2944-9488 surname: Chelariu-Raicu fullname: Chelariu-Raicu, Anca organization: Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany – sequence: 17 givenname: Tsun Hsuan surname: Chen fullname: Chen, Tsun Hsuan organization: Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 18 givenname: Nashwa surname: Kabil fullname: Kabil, Nashwa organization: AstraZeneca, Gaithersburg, Maryland – sequence: 19 givenname: Pamela T surname: Soliman fullname: Soliman, Pamela T organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 20 givenname: Michael surname: Frumovitz fullname: Frumovitz, Michael organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 21 givenname: Katheleen M surname: Schmeler fullname: Schmeler, Katheleen M organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 22 givenname: Amir orcidid: 0000-0003-4335-4151 surname: Jazaeri fullname: Jazaeri, Amir organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 23 givenname: Karen H surname: Lu fullname: Lu, Karen H organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 24 givenname: Rashmi orcidid: 0000-0002-0103-4718 surname: Murthy fullname: Murthy, Rashmi organization: Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 25 givenname: Larissa A orcidid: 0000-0002-2687-7463 surname: Meyer fullname: Meyer, Larissa A organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 26 givenname: Charlotte C surname: Sun fullname: Sun, Charlotte C organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 27 givenname: Anil K surname: Sood fullname: Sood, Anil K organization: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 28 givenname: Robert L orcidid: 0000-0001-9343-8754 surname: Coleman fullname: Coleman, Robert L organization: US Oncology Research, The Woodlands, Texas – sequence: 29 givenname: Gordon B orcidid: 0000-0002-0144-9614 surname: Mills fullname: Mills, Gordon B organization: Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon |
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| SubjectTerms | Antineoplastic Combined Chemotherapy Protocols - adverse effects Female Humans Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Phthalazines Piperazines Pyrimidines Pyrroles Triple Negative Breast Neoplasms - drug therapy |
| Title | Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer |
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