P103 USE OF THE CONJUNCTIVAL PROVOCATION TEST AS PRIMARY ENDPOINT FOR PHASE II DOSE RESPONSE STUDIES

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Dual immune checkpoint blockade in advanced well-differentiated neuroendocrine tumors, a phase II clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16201 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16201-e16201

Author(s):

Susan Combs Scott ◽

Ana De Jesus-Acosta ◽

Chen Hu ◽

Benjamin Philip Levy ◽

Valsamo Anagnostou ◽

...

Keyword(s):

Clinical Trial ◽

Neuroendocrine Tumors ◽

Phase Ii ◽

Median Duration ◽

Primary Endpoint ◽

Response Rate ◽

Objective Response ◽

Phase Ii Clinical Trial ◽

Open Label ◽

Well Differentiated

e16201 Background: Limited systemic treatment options are available for progressive well-differentiated neuroendocrine tumors (NET), also called carcinoid tumors. Given emerging evidence for immunotherapy response in high grade NET including small cell lung cancer, we sought to determine the efficacy of combination immunotherapy with ipilimumab and nivolumab in patients with advanced, progressive, well-differentiated NET in an open label phase II clinical trial. Methods: Eligible patients had well-differentiated, nonfunctional NET of lung, pancreas, or GI origin that had progressed within the past 12 months after at least one line of prior therapy. Patients received nivolumab 240 mg every 2 weeks and ipilimumab 1mg/kg every 6 weeks for up to 2 years. Primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon’s 2-stage design, the study planned to accrue up to 56 patients. Based on published response rates to everolimus of 5%, we hypothesized that this regimen would be considered promising if the true ORR is > 15%. Results: Nine patients were enrolled prior to study closure due to funding, including 6 patients with NET of lung origin, 2 pancreatic, and 1 small bowel (Table). Median age was 71 years. All patients had distant metastatic disease at enrollment, with an average of 2 prior lines of therapy. Four of 9 patients achieved the primary endpoint of confirmed objective response, all of whom have ongoing response with a median duration of 15.4 months. Five of 9 patients, including all 4 responders, experienced immune-related toxicity requiring treatment modification or discontinuation. The trial did not accrue the target of 56 patients, however, objective response in 4 of 9 patients (ORR 44.4%, 90% CI: 16.9-74.9%) excluded the response rate target (15%). Conclusions: The impressive ORR of 44% with a median duration of response exceeding 15 months in this small clinical trial warrants further study of combination CTLA-4 and PD-1 inhibition in previously treated well-differentiated NET. Our ongoing immunologic and genomic correlative analysis in responders and non-responders will help inform future study of immunotherapy in this patient population in need of new systemic therapy approaches. Clinical trial information: NCT03420521. [Table: see text]

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ICEPAC: A phase II multicenter study of avelumab combined with stereotactic ablative body radiotherapy (SABR) in metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.86 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 86-86

Author(s):

Arun Azad ◽

Lavinia Anne Spain ◽

Angelyn Anton ◽

Chun Loo Gan ◽

Linda Garrett ◽

...

Keyword(s):

Soft Tissue ◽

Disease Control ◽

Phase Ii ◽

Primary Endpoint ◽

Checkpoint Inhibitors ◽

Disease Assessment ◽

Castration Resistant Prostate Cancer ◽

Protocol Amendment ◽

Stereotactic Ablative Body Radiotherapy ◽

Taxane Chemotherapy

86 Background: Studies investigating immune checkpoint inhibitors (ICI) in mCRPC have produced modest results. Radiation therapy may be synergistic with ICIs. We hypothesised that SABR would enhance anti-tumour activity of PD-L1 inhibitor avelumab in patients (pts) with progressive mCRPC. Methods: This phase II, single arm, multicentre study enrolled mCRPC pts following progression on ≥1 novel androgen receptor-directed therapy. Up to two lines of prior taxane chemotherapy were permitted. Pts received avelumab 10mg/kg IV q2weeks for a total of 24 weeks (12 cycles). A single fraction of 20Gy SABR was administered to 1-2 disease sites within five days prior to first and second doses of avelumab. Primary endpoint was disease control rate (DCR); secondary endpoints were PSA response (PSA50), overall response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS) and safety. Radiographic disease assessment (CT and bone scintigraphy) was performed after cycles 6 and 12 of avelumab treatment. Following enrolment of 14 pts, a protocol amendment allowed avelumab beyond 12 cycles in pts with disease control at 24 weeks. Results: Thirty-one pts were enrolled, with 30 evaluable for the primary endpoint. Median follow-up was 18 months (mo). Pt characteristics: median age 71 years (IQR 64-75), bone-only disease 42%, visceral disease 16%, prior taxane chemotherapy 84%, treatment with both abiraterone and enzalutamide 13%. Seventy metastatic sites received SABR, most frequently to bone (90%) and soft tissue (29%) disease. Avelumab was given as second-line, third-line and fourth- or greater line systemic therapy in 29%, 42% and 29% of pts, respectively. Median cycles of avelumab administered was 9 (IQR 5-13). DCR (95% CI) was 50% (31-69) and 60% (32-84) in all-comers and soft tissue disease subgroup, respectively. Following protocol amendment, 7/17 pts (41%) received avelumab beyond 12 cycles. Incidence of grade 3-4 treatment-related AEs was 16% (no grade 5 events), with three pts requiring oral/IV corticosteroid therapy. Conclusions: Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile. This combination warrants further investigation. Clinical trial information: ACTRN12618000954224. [Table: see text]

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Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3506 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3506-3506

Author(s):

Andrea Sartore-Bianchi ◽

Filippo Pietrantonio ◽

Sara Lonardi ◽

Benedetta Mussolin ◽

Francesco Rua ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Primary Endpoint ◽

Liquid Biopsy ◽

Objective Response ◽

Circulating Tumor Dna ◽

Type I ◽

Tumor Dna

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

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Randomized phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6015 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6015-6015

Author(s):

Julie E. Bauman ◽

Nabil F. Saba ◽

Denise Roe ◽

Jessica R. Bauman ◽

John M. Kaczmar ◽

...

Keyword(s):

Lower Bound ◽

Phase Ii ◽

Primary Endpoint ◽

Performance Status ◽

Primary Objective ◽

Phase Iii ◽

Platinum Resistance ◽

Eligibility Criteria ◽

Immune Biomarkers ◽

Hpv Status

6015 Background: Cetuximab (C), an anti-EGFR monoclonal antibody (mAb), is approved for advanced HNSCC but benefits a minority. Crosstalk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways is a known resistance mechanism. HGF is also immunosuppressive within the tumor microenvironment. A Phase I study confirmed the safety of C and ficlatuzumab (F), an IgG1 anti-HGF mAb, with preliminary efficacy and biomarker data suggesting that dual pathway inhibition may overcome tumor-intrinsic or immune cetuximab resistance. Methods: The primary objective of this phase II randomized, non-comparative trial was to evaluate the efficacy of F (20 mg/kg every 2 wks), with or without C (500 mg/m2 every 2 wks), in pan-refractory, advanced HNSCC. Eligibility criteria included recurrent/metastatic HNSCC, performance status (PS) 0-1, C resistance (defined as progression on or within 6 months of exposure), and resistance to or ineligibility for platinum and anti-PD1 mAb. Randomization was stratified by HPV status and center. The primary endpoint was median progression-free survival (mPFS). An arm was deemed worthy of further study if the lower bound of the 90% 1-sided confidence interval (CI) excluded the historical control of 2 months. Secondary objectives included overall response rate (ORR) in the overall and HPV-stratified populations. A Bayesian continuous monitoring rule for futility was applied. Results: 60 patients were randomized and 58 treated between Jan 2018 and Dec 2020 (27 to F; 33 to FC). Baseline characteristics were balanced across major prognostic variables including age, PS, HPV status, platinum resistance, and PD1 mAb exposure. Median time since prior cetuximab was 3.5 months (range 0-48 months). Grade ≥3 adverse events attributed to F included: pneumonitis (2); edema (3); diarrhea (1); LFT elevation (1); rash (2); electrolyte abnormality (2). The Table presents efficacy data. The F arm stopped for futility after 26 evaluable subjects accrued. The FC arm completed accrual and met the primary endpoint; 32 evaluable subjects had mPFS of 3.6 months (lower bound 90% 1-sided CI: 2.3 months) and ORR of 19% (6/32). All responses were in HPV- subjects, including 2 complete (CR) and 4 partial responses (PR) to the FC combination and 1 PR to F monotherapy. The mPFS and ORR for the HPV- population (n = 16) on FC were 3.8 months and 38% (6/16). Mechanistic signaling and immune biomarkers are under analysis. Conclusions: The well-tolerated FC combination met the primary PFS endpoint in pan-refractory, advanced HNSCC with notable activity in HPV- HNSCC, warranting phase III investigation. Clinical trial information: NCT03422536. [Table: see text]

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