Oncology Daily Report: 01/17/2024

Phase 3 studies

Acute Myeloid Leukemia

A randomized phase 3 study, the ASTRAL-2 trial (NCT02920008), investigated the effect of guadecitabine vs a treatment choice (TC) in 302 patients with relapsed/refractory AML (1). The median overall survival (OS) was 6.4 months for guadecitabine and 5.4 months for TC (hazard ratio 0.88 [95% CI 0.67, 1.14]; log-rank P=0.33). Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC (P<0.01), and CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC (P<0.01). However, the study did not demonstrate an OS benefit for guadecitabine over TC.

Reference

Roboz GJ, Sanz GF, Griffiths EA, Yee KWL, Kantarjian HM, Récher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illes A, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell C, Hao Y, Keer HN, Azab M, Döhner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Jan 17:bloodadvances.2023012062. doi: 10.1182/bloodadvances.2023012062. Epub ahead of print. PMID: 38231126.

Pancreatic Ductal Adenocarcinoma (metastatic)

A randomized phase III PRODIGE 65-UCGI 36-GEMPAX study investigated the effect of Gemcitabine and Paclitaxel versus Gemcitabine alone in 211 patients with metastatic pancreatic ductal adenocarcinoma and found that the median overall survival (OS) was 6.4 versus 5.9 months, the median progression-free survival (PFS) was 3.1 versus 2.0 months, and the objective response rate (ORR) was 17.1% versus 4.2% for the combination versus gemcitabine alone, respectively (1).

Reference

De La Fouchardière C, Malka D, Cropet C, Chabaud S, Raimbourg J, Botsen D, Launay S, Evesque L, Vienot A, Perrier H, Jary M, Rinaldi Y, Coutzac C, Bachet JB, Neuzillet C, Williet N, Desgrippes R, Grainville T, Aparicio T, Peytier A, Lecomte T, Roth GS, Thirot-Bidault A, Lachaux N, Bouché O, Ghiringhelli F. Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study. J Clin Oncol. 2024 Jan 17:JCO2300795. doi: 10.1200/JCO.23.00795. Epub ahead of print. PMID: 38232341.

Large B Cell Lymphoma

The phase 3 ZUMA-7 trial investigated the efficacy of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel) compared to standard of care (salvage chemotherapy followed by hematopoietic transplantation) in large B cell lymphoma (1). The study found B cell gene expression signature and CD19 expression significantly associated with improved event-free survival for axi-cel but not standard of care. Axi-cel showed superior event-free survival over standard of care irrespective of B cell gene expression signature and CD19 expression.

Reference

Locke FL, Filosto S, Chou J, Vardhanabhuti S, Perbost R, Dreger P, Hill BT, Lee C, Zinzani PL, Kröger N, López-Guillermo A, Greinix H, Zhang W, Tiwari G, Budka J, Marincola FM, To C, Mattie M, Schupp M, Cheng P, Bot A, Shen R, Bedognetti D, Miao H, Galon J. Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma. Nat Med. 2024 Jan 17. doi: 10.1038/s41591-023-02754-1. Epub ahead of print. PMID: 38233586.

Phase 2 studies

Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS)

A phase II single arm, open label, multicenter study investigated the effect of ribociclib combined with everolimus in patients with DDL or LMS with intact Rb (1). The DDL cohort showed a progression-free rate (PFR) of 33.3% at 16 weeks, median PFS of 15.4 weeks, and 2 partial responses. The LMS cohort had a PFR of 29.2% at 16 weeks, with a median PFS of 15.7 weeks. Common toxicities included fatigue, anorexia, and hyperglycemia.

Reference

Movva S, Matloob S, Handorf EA, Choy E, Merriam P, Flieder DB, Cai KQ, Zhou Y, Tetzlaff ED, Pagan C, Barker E, Veggeberg R, Zumpano D, Rink L, von Mehren M, George S. SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS). Clin Cancer Res. 2024 Jan 17;30(2):315-322. doi: 10.1158/1078-0432.CCR-23-2469. PMID: 37967116.

Glioblastoma

A phase II single-arm study investigated the effect of pharmacologic ascorbate (P-AscH-) combined with radiation and temozolomide in 55 patients with GBM. The study, registered as NCT02344355, found a median overall survival (OS) of 19.6 months (90% CI, 15.7-26.5 months), which was a statistically significant increase compared to historic control patients (14.6 months) (1). Patients with initial T2* relaxation < 50 ms showed a significant increase in progression-free survival (PFS) (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months).

Reference

Petronek MS, Monga V, Bodeker KL, Kwofie M, Lee CY, Mapuskar KA, Stolwijk JM, Zaher A, Wagner BA, Smith MC, Vollstedt S, Brown H, Chandler ML, Lorack AC, Wulfekuhle JS, Sarkaria JN, Flynn RT, Greenlee JDW, Howard MA, Smith BJ, Jones KA, Buettner GR, Cullen JJ, St-Aubin J, Buatti JM, Magnotta VA, Spitz DR, Allen BG. Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM. Clin Cancer Res. 2024 Jan 17;30(2):283-293. doi: 10.1158/1078-0432.CCR-22-3952. PMID: 37773633.

Muscle-Invasive Bladder Cancer

A phase II study investigated the association of molecular subtypes with pathologic response, progression-free survival (PFS), and overall survival (OS) in 237 patients with muscle-invasive bladder cancer receiving neoadjuvant chemotherapy (NAC) (1). The study found that the Consensus classifier modestly improved prediction for pathologic downstaging but subtypes were not associated with PFS or OS.

Reference

Lerner SP, McConkey DJ, Tangen CM, Meeks JJ, Flaig TW, Hua X, Daneshmand S, Alva AS, Lucia MS, Theodorescu D, Goldkorn A, Milowsky MI, Choi W, Bangs R, Gustafson DL, Plets M, Thompson IM Jr. Association of Molecular Subtypes with Pathologic Response, PFS, and OS in a Phase II Study of COXEN with Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer. Clin Cancer Res. 2024 Jan 17;30(2):444-449. doi: 10.1158/1078-0432.CCR-23-0602. PMID: 37966367.

Phase 1/2 studies

High-Risk Leukemia or Myelodysplastic Syndrome

A phase I/II study (ClinicalTrials.gov, NCT00589316) investigated iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning before HLA-haploidentical HCT in 25 adults with high-risk relapsed/refractory acute myeloid or lymphoid leukemia (AML or ALL), or MDS (1). All patients achieved morphologic remission 28 days after HCT, with median engraftment times of 15 days for neutrophils and 23 days for platelets. One-year overall survival and progression-free survival were 40% and 32%, and two-year overall survival was 24%.

Reference

Orozco JJ, Vo PT, Gooley TA, Haaf RL, Lundberg SJ, Hamlin DK, Wilbur DS, Matesan MC, Fisher DR, Gopal AK, Green DJ, Pagel JM, Sandmaier BM. Targeted Radiation Delivery before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-term Survivors. Clin Cancer Res. 2024 Jan 17;30(2):274-282. doi: 10.1158/1078-0432.CCR-23-1200. PMID: 37939122.

Hormone Receptor-Positive/HER2-Negative Advanced or Metastatic Breast Cancer

A phase I/II study investigated the effect of Molibresib combined with fulvestrant in 123 patients with HR+/HER2- advanced/metastatic breast cancer and found an objective response rate (ORR) of 13% (1). Grade 3 or 4 treatment-related adverse events were observed in 47% and 48% of patients treated with Molibresib 60 mg and 80 mg, respectively. The study concluded that Molibresib combined with fulvestrant did not demonstrate clinically meaningful activity.

Reference

Cescon DW, Hilton J, Morales Murilo S, Layman RM, Pluard T, Yeo B, Park IH, Provencher L, Kim SB, Im YH, Wyce A, Krishnatry AS, Hicks K, Zhang Q, Barbash O, Khaled A, Horner T, Dhar A, Oliveira M, Sparano JA. A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer. Clin Cancer Res. 2024 Jan 17;30(2):334-343. doi: 10.1158/1078-0432.CCR-23-0133. PMID: 37992310; PMCID: PMC10792358.

Pancreatic Ductal Adenocarcinoma (advanced)

A phase I/IIa ENG9 clinical trial investigated the effect of EGFR-targeted, PNU-159682-packaged nanocells with α-galactosyl ceramide-packaged nanocells (E-EDV-D682/GC) in 25 patients with advanced pancreatic ductal adenocarcinoma and found that the median overall survival (mOS) was 4.4 months overall, and 6.9 months for patients completing one treatment cycle (1). 47.1% achieved stable disease and one partial response, with significant overall survival, minimal side effects, and weight stabilization.

Reference

Ganju V, Marx G, Pattison S, Amaro-Mugridge NB, Zhao JT, Williams BRG, MacDiarmid JA, Brahmbhatt H. Phase I/IIa Trial in Advanced Pancreatic Ductal Adenocarcinoma Treated with Cytotoxic Drug-Packaged, EGFR-Targeted Nanocells and Glycolipid-Packaged Nanocells. Clin Cancer Res. 2024 Jan 17;30(2):304-314. doi: 10.1158/1078-0432.CCR-23-1821. PMID: 37976042.

Phase 1 studies

Chordoma

A pilot single-group assignment study investigated the effect of high-dose pemetrexed in 15 patients with progressive chordoma and found that high-dose pemetrexed appears tolerable and shows objective antitumor activity, with a median PFS of 10.5 months and 6-month PFS of 67% (1).

Reference

Kesari S, Wagle N, Carrillo JA, Sharma A, Nguyen M, Truong J, Gill JM, Nersesian R, Nomura N, Rahbarlayegh E, Barkhoudarian G, Sivakumar W, Kelly DF, Krauss H, Bustos MA, Hoon DSB, Anker L, Singh AS, Sankhala KK, Juarez TM. Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma. Clin Cancer Res. 2024 Jan 17;30(2):323-333. doi: 10.1158/1078-0432.CCR-23-2317. PMID: 38047868.

Head and Neck Squamous Cell Carcinoma (locally advanced)

A phase I dose-escalation study (NCT03024489) investigated the effect of palbociclib in combination with cetuximab and intensity-modulated radiotherapy (IMRT) in 27 patients with LA-HNSCC (1). The recommended phase II dose (RP2D) was 125 mg/day palbociclib for 21 days per cycle, for two cycles during IMRT. Common grade 3-4 toxicities were mucositis, radiation dermatitis, and neutropenia. The objective response rate was 84%, with 2-year locoregional control, event-free survival, and overall survival rates of 73%, 48%, and 71%, respectively.

Reference

Ngamphaiboon N, Pattaranutaporn P, Lukerak S, Siripoon T, Jinawath A, Arsa L, Shantavasinkul PC, Taonam N, Trachu N, Jinawath N, Kositwattanarerk A, Sananmuang T, Jiarpinitnun C. A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2024 Jan 17;30(2):294-303. doi: 10.1158/1078-0432.CCR-23-2303. PMID: 37982827.

High Grade Gliomas

A phase 1 trial investigated the effect of mebendazole in combination with bevacizumab and irinotecan in 10 children and young adults with high-grade gliomas (HGG), and found no dose-limiting toxicities, with the most frequent G3/4 adverse events being neutropenia and lymphopenia (1) The overall response rate was 33%, with two subjects achieving a partial response and one a complete response sustained for 10 months. The mean progression-free survival (PFS) and overall survival (OS) from the start of study treatment were 4.7 and 11.4 months, respectively.

Reference

Krystal J, Hanson D, Donnelly D, Atlas M. A phase 1 study of mebendazole with bevacizumab and irinotecan in high-grade gliomas. Pediatr Blood Cancer. 2024 Jan 17:e30874. doi: 10.1002/pbc.30874. Epub ahead of print. PMID: 38234020.

KRAS-mutant Metastatic Colorectal Cancer

A phase 1b clinical study investigated the effect of Onvansertib combined with FOLFIRI and bevacizumab in 18 patients with KRAS-mutant metastatic colorectal cancer previously treated with oxaliplatin and found partial responses in 44% of patients with a median duration of response of 9.5 months (1). Grade 3 and 4 adverse events represented 15% of all treatment-related AEs, with neutropenia being the most common.

Reference

Ahn DH, Barzi A, Ridinger M, Samuëlsz E, Subramanian RA, Croucher PJP, Smeal T, Kabbinavar FF, Lenz HJ. Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-line Treatment of KRAS-mutant Metastatic Colorectal Cancer: A Phase 1b Clinical Study. Clin Cancer Res. 2024 Jan 17. doi: 10.1158/1078-0432.CCR-23-3053. Epub ahead of print. PMID: 38231047.

Laryngeal and Hypopharyngeal Cancer (locally advanced)

A single-arm phase II clinical trial assessed induction chemotherapy combined with PD-1 inhibitor toripalimab in 27 patients with locally advanced laryngeal/hypopharyngeal squamous cell carcinoma (1). The overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months post-radiation, the larynx preservation rate was 88.9%. The 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively.

Reference

Ou X, Zhai R, Wei W, Chen J, Ou D, Liao T, Xu T, Zhu Y, Wang Y, Huang S, Shi R, Wu B, Chen T, Li Y, Yang Z, Zhou C, Liu Y, Jiang Z, Zeng M, Liu X, Ji D, Ying H, Zhang Z, Hu C, Lu X, Ji Q, He X, Wang Y. Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial. Clin Cancer Res. 2024 Jan 17;30(2):344-355. doi: 10.1158/1078-0432.CCR-23-2398. PMID: 37955629.

Clear Cell Renal Cell Carcinoma (non-metastatic)

A phase I trial investigated the effect of neoadjuvant nivolumab in 15 evaluable patients with non-metastatic ccRCC (1). The study found that nivolumab induced a pro-inflammatory state within the primary tumor, increased CTLA-4 expression in the tumor, and led to increased circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These results suggest a potential for neoadjuvant immune checkpoint inhibition (ICI) in high-risk ccRCC.

Reference

Singla N, Nirschl TR, Obradovic AZ, Shenderov E, Lombardo K, Liu X, Pons A, Zarif JC, Rowe SP, Trock BJ, Hammers HJ, Bivalacqua TJ, Pierorazio PM, Deutsch JS, Lotan TL, Taube JM, Ged YMA, Gorin MA, Allaf ME, Drake CG. Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma. Sci Rep. 2024 Jan 17;14(1):1458. doi: 10.1038/s41598-024-51889-9. PMID: 38228729; PMCID: PMC10792074.