Clinical Situation: Platinum-Resistant/Refractory Recurrence

Platinum-Resistant/Refractory (Pt-R/Rf): Treatment given for recurrence occurring less than 6 months after last platinum-based treatment or for progression during last platinum-based treatment

Platinum-Resistant/Refractory (Pt-R/Rf): Treatment given for recurrence occurring less than 6 months after last platinum-based treatment or for progression during last platinum-based treatment

For more detailed information, please click on the clinical trial ID number.

Drug Class Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Standard of Care Chemotherapy
Chemotherapy NCT00023907; NCT00191607; Study 30-49; ITSG II/III Gemcitabine, Liposomal doxorubicin, Paclitaxel, Topotecan Compilation of multiple single drug chemotherapy trials for platinum-resistant recurrence

Similar response rates for single-agent gemcitabine, liposomal doxorubicin, topotecan or paclitaxel

ORR: median 8% (6.1-20.9%)
PFS: median 3.3 months (2.3-4.3 months)

v. 9/2017

Standard of Care Targeted Drugs
DNA Damage Repair Pathway Inhibitors:PARP NCT01078662 II Olaparib A Phase II, Open Label, Non Randomised, Non Comparative, Multicentre Study to Assess the Efficacy and Safety of Olaparib Given Orally Twice Daily in Patients With Advanced Cancers Who Have a Confirmed Genetic BRCA 1 and/or BRCA2 Mutation (Study 42)

Olaparib shows promising responses in heavily pretreated gBRCA MUT patients

ORR: 30%
PFS: 5.5 months

v. 9/2018

DNA Damage Repair Pathway Inhibitors:PARP Rucaparib FDA Approval Data II Rucaparib Treatment of BRCA-mutated Ovarian Cancer After 2 or More Chemotherapies

Rucaparib shows promising responses in BRCA MUT patients

ORR: 25%

v. 9/2018

Angiogenesis Inhibitors: VEGF NCT00976911 III Bevacizumab, Liposomal doxorubicin, Paclitaxel, Topotecan AURELIA: A Multi-center, Open-label, Randomised, Two-arm Phase III Trial of the Effect on Progression Free Survival of Bevacizumab Plus Chemotherapy Versus Chemotherapy Alone in Patients With Platinum-resistant, Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer

Improved ORR and PFS with addition of bevacizumab to liposomal doxorubicin, paclitaxel or topotecan (most evident with paclitaxel), but no OS benefit

Pac/PLD/Top+Bev vs Pac/PLD/Top:

ORR: 28.2 vs 12.5%*
PFS: 6.7 vs 3.4 months*

v. 1/2017

Drugs in NCCN Guidelines
Chemotherapy NCT00087087 II Pemetrexed A Phase II Evaluation of Pemetrexed (Alimta, LY231514l, IND # 40061) in the Treatment of Recurrent or Persistent Platinum Resistant Ovarian or Primary Peritoneal Carcinoma

Pemetrexed has favorable antitumor activity with mild and non-cumulative toxicity

ORR: 21.4%
PFS: 2.9 months

v. 5/2018

Angiogenesis Inhibitors: VEGF NCT00097019 II Bevacizumab A Multicenter, Single-Arm, Phase II Trial of Bevacizumab in Subjects With Platinum-Resistant Epithelial Carcinoma of the Ovary or Primary Peritoneal Carcinoma for Whom Subsequent Doxil or Topotecan Therapy Has Failed

Bevacizumab single-agent activity in platinum-resistant patients, but risk of GI-related adverse events

ORR: 15.9%
PFS: 4.4 months
OS: 10.7 months

v. 7/2017

Angiogenesis Inhibitors: VEGFR/PDGFR NCT01644825 II Paclitaxel, Pazopanib MITO-11: A Randomized Multicentre Phase II Trial With Pazopanib and Weekly Paclitaxel vs Weekly Paclitaxel in Platinum Resistant or Refractory Ovarian Cancer

Improved ORR and PFS with combination of pazopanib+paclitaxel

Pac+Paz vs Pac:

ORR: 56 vs 25%*
PFS: 6.35 vs 3.49 months*

v. 1/2017

Drugs in Clinical Development
DNA Damage Repair Pathway Inhibitors:PARP NCT01540565 II Veliparib A Phase II Evaluation of the Poly (ADP-Ribose) Polymerase (PARP)-1 and -2 Inhibitor Veliparib (ABT-888) (NSC#737664) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients Who Carry a Germline BRCA1 or BRCA2 Mutation

Veliparib shows encouraging activity in gBRCA MUT cancer

ORR: 20%
PFS: 5.8 months

v. 1/2017

DNA Damage Repair Pathway Inhibitors:PARP NCT02354586 II Niraparib A Phase 2, Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of Niraparib in Patients With Advanced, Relapsed, High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Have Received Three or Four Previous Chemotherapy Regimens (QUADRA)

Niraparib shows promising activity in late-line treatment setting

BRCA MUT:
ORR: 27%
HRD-positive (incl. BRCA MUT):
ORR: 10%

v. 11/2018

DNA Damage Repair Pathway Inhibitors:PARP NCT02657889 I/II Niraparib, Pembrolizumab Phase 1/2 Clinical Study of Niraparib in Combination With Pembrolizumab (MK-3475) in Patients With Advanced or Metastatic Triple-Negative Breast Cancer and in Patients With Recurrent Ovarian Cancer (TOPACIO)

Promising activity of niraparib + pembrolizumab combination in Pt-R/Pt-Rf patients independent of BRCA status, HRD status and PD-L1 expression

BRCA WT:
ORR: 24%
HRD-negative:
ORR: 27%

v. 6/2018

Antibody (and other Targeted) Drug Conjugates: FRalpha NCT01609556 I Mirvetuximab Soravtansine A Phase 1, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of IMGN853 in Adults With Ovarian Cancer and Other FOLR1-Positive Solid Tumors

Mirvetuximab soravtansine shows promising activity in platinum-resistant FRalpha-positive patients who had ≤3 prior therapies

≤3 prior therapies vs >3 prior therapies:

ORR: 39 vs 13%
PFS: 6.7 vs 3.9 months

v. 8/2018

Antibody (and other Targeted) Drug Conjugates: Mesothelin NCT02751918 Ib Anetumab ravtansine, Liposomal doxorubicin An Open-label Phase Ib Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Maximum Tolerated Dose of Anetumab Ravtansine in Combination With Pegylated Liposomal Doxorubicin 30 mg/m2 Given Every 3 Weeks in Subjects With Mesothelin-expressing Platinum-resistant Recurrent Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Anetumab ravtansine+liposomal doxorubicin combination shows promising activity in platinum-resistant mesothelin-positive patients

ORR: 52%
PFS: 5.5 months

v. 6/2018

Angiogenesis Inhibitors: VEGF NCT02606305 Ib Bevacizumab, Mirvetuximab Soravtansine A Phase 1b/2 Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Mirvetuximab Soravtansine (IMGN853) in Combination With Bevacizumab, Carboplatin, Pegylated Liposomal Doxorubicin, Pembrolizumab, or Bevacizumab+Carboplatin in Adults With Folate Receptor Alpha Positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer

Encouraging activity of bevacizumab+mirvetuximab soravtansine combination in FRalpha-positive patients

ORR: 43%
PFS: 7.8 months

v. 8/2018

Angiogenesis Inhibitors: VEGF/DLL4 NCT03030287 Ib Navicixizumab, Paclitaxel A Phase 1b Study of OMP-305B83 Plus Weekly Paclitaxel in Subjects With Platinum Resistant Ovarian, Primary Peritoneal or Fallopian Tube Cancer

Promising activity of navicixizumab+paclitaxel combination in heavily pretreated patients

ORR: 42%
PFS: 5.4 months

Signaling Pathway Inhibitors: PI3K-AKT-mTOR/pan-PI3K NCT01623349 I Buparlisib, Olaparib Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent Triple Negative Breast Cancer or Recurrent High Grade Serous Ovarian Cancer

Encouraging activity of buparlisib+olaparib, but serious CNS adverse events

ORR: 27%

v. 5/2017

Signaling Pathway Inhibitors: PI3K-AKT-mTOR/PI3Kalpha NCT01623349 I Alpelisib, Olaparib Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent Triple Negative Breast Cancer or Recurrent High Grade Serous Ovarian Cancer

Encouraging activity of alpelisib+olaparib combination independent of gBRCA status

ORR: 36%

v. 5/2017

Signaling Pathway Inhibitors: JAK-STAT/STAT3 NCT01325441 II Napabucasin, Paclitaxel A Phase Ib/II Clinical Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies

Promising responses to napabucasin+paclitaxel in heavily pretreated patients

ORR: 20%
DCR (6 months): 27%

v. 6/2018

Cell Cycle Inhibitors: CHK1/2 NCT02203513 II Prexasertib A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) In BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, and High Grade Serous Ovarian Cancer

Promising activity in heavily pretreated platinum-resistant gBRCA WT patients, including those with CCNE1 aberrations

ORR: 32%
PFS: 7.5 months

v. 6/2018

Cell Cycle Inhibitors: Wee1 NCT01164995 II Adavosertib, Carboplatin Phase II Pharmacological Study With Wee-1 Inhibitor MK-1775 Combined With Carboplatin in Patients With p53 Mutated Epithelial Ovarian Cancer and Early Relapse (< 3 Months) or Progression During Standard First Line Treatment

Promising activity of adavosertib+carboplatin combination in TP53-mutated primary platinum-resistant and platinum-refractory patients

ORR: 43%
PFS: 5.3 months

v. 8/2018

Immunotherapy: Checkpoint Inhibitors/PD-1 NCT02865811 II Liposomal doxorubicin, Pembrolizumab A Phase II Study of Pembrolizumab Combined With Pegylated Liposomal Doxorubicin (PLD) For Recurrent Platinum Resistant Ovarian, Fallopian Tube Or Peritoneal Cancer

Encouraging anti-tumor activity of pembrolizumab+liposomal doxorubicin combination with acceptable safety profile

ORR: 19%
DCR: (6 months): 42%

v. 4/2018

Immunotherapy: Checkpoint Inhibitors/PD-1 UMIN000005714 II Nivolumab A Phase II trial of immunotherapy with an anti-PD-1 antibody in advanced / relapsed, Platinum - resistant Ovarian Cancer

Encouraging anti-tumor activity of single-agent nivolumab with acceptable safety profile

ORR: 15%
DCR: 45%
PFS: 3.5 months

v.1/2017

Immunotherapy: Checkpoint Inhibitors/PD-1 NCT02606305 Ib Mirvetuximab Soravtansine, Pembrolizumab A Phase 1b/2 Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Mirvetuximab Soravtansine (IMGN853) in Combination With Bevacizumab, Carboplatin, Pegylated Liposomal Doxorubicin, Pembrolizumab, or Bevacizumab+Carboplatin in Adults With Folate Receptor Alpha Positive Advanced Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer

Encouraging activity of pembrolizumab + mirvetuximab soravtansine combination in FRalpha-positive patients

ORR: 30%
PFS: 4.2 months

v. 11/2018

Immunotherapy: Checkpoint Inhibitors/PD-1 NCT01772004 I Avelumab A Phase I, Open-label, Multiple-ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Subjects With Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications

Avelumab shows encouraging activity with acceptable safety profile

ORR: 9.7%
DCR: 54.0%
PFS: 2.8 months

v. 6/2018

Immunotherapy: Checkpoint Inhibitors/PD-1 NCT02054806 I Pembrolizumab Phase IB Study of MK-3475 in Subjects With Select Advanced Solid Tumors

Pembrolizumab shows encouraging anti-tumor activity with acceptable safety profile

ORR:12%
DCR: 35%
PFS: 1.9 months

v. 11/2017

Immunotherapy: Checkpoint Inhibitors/PD-L1 NCT02580058 III Avelumab, Liposomal doxorubicin A Phase 3, Multicenter, Randomized, Open-Label Study Of Avelumab (MSB0010718C) Alone Or In Combination With Pegylated Liposomal Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone In Patients With Platinum-Resistant/Refractory Ovarian Cancer

Avelumab alone or in combination with liposomal doxorubicin does not significantly improve ORR, PFS or OS versus PLD alone

PLD vs Ave vs Ave+PLD:

ORR: 4.2 vs 3.7 vs 13.3%

v. 11/2018

Immunotherapy: Checkpoint Inhibitors/PD-L1 NCT02431559 II Durvalumab, Liposomal doxorubicin A Phase 1/2 Study of Chemo-immunotherapy With Toll-like Receptor 8 Agonist Motolimod (VTX-2337) and Anti-PD-L1 Antibody MEDI4736 in Subjects With Recurrent, Platinum-Resistant Ovarian Cancer for Whom Pegylated Liposomal Doxorubicin (PLD) is Indicated

The combination of durvalumab+liposomal doxorubicin has a tolerable safety profile and promising efficacy

ORR: 15%
PFS: 5.5 months

v. 11/2018

*Statistically significant result

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