Pius Maliakal

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors

Purpose: Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers. Experimental Design: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Results: Twenty-five patients (52–60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done. Conclusions: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies. Clin Cancer Res; 21(17); 3870–8. ©2015 AACR.

Tolfenamic acid inhibits neuroblastoma cell proliferation and induces apoptosis: A novel therapeutic agent for neuroblastoma

Current therapeutic options for recurrent neuroblastoma have poor outcomes that warrant the development of novel therapeutic strategies. Specificity protein (Sp) transcription factors regulate several genes involved in cell proliferation, survival, and angiogenesis. Sp1 regulates genes believed to be important determinants of the biological behavior of neuroblastoma. Tolfenamic acid (TA), a non‐steroidal anti‐inflammatory drug, is known to induce the degradation of Sp proteins and may serve as a novel anti‐cancer agent. The objective of this investigation was to examine the anti‐cancer activity of TA using established human neuroblastoma cell lines. We tested the anti‐proliferative effect of TA using SH‐SY5Y, CHLA90, LA1 55n, SHEP, Be2c, CMP 13Y, and SMS KCNR cell lines. Cells were treated with TA (0/25/50/100 µM) and cell viability was measured at 24, 48, and 72 h post‐treatment. Selected neuroblastoma cell lines were treated with 50 µM TA for 24 and 48 h and tested for cell apoptosis using Annexin‐V staining. Caspase activity was measured with caspase 3/7 Glo kit. Cell lysates were prepared and the expression of Sp1, survivin, and c‐PARP were evaluated through Western blot analysis. TA significantly inhibited the growth of neuroblastoma cells in a dose/time‐dependent manner and significantly decreased Sp1 and survivin expression. Apart from cell cycle (G0/G1) arrest, TA caused significant increase in the apoptotic cell population, caspase 3/7 activity, and c‐PARP expression. These results show that TA effectively inhibits neuroblastoma cell growth potentially through suppressing mitosis, Sp1, and survivin expression, and inducing apoptosis. These results show TA as a novel therapeutic agent for neuroblastoma.

Abstract CT206: SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results

IMMU-132 is an ADC of the active metabolite of CPT-11, SN-38, conjugated by a pH-sensitive linker (average drug-antibody ratio = 7.6) to the humanized anti-Trop-2 antibody, hRS7, exhibiting rapid internalization after binding to Trop-2. Trop-2 is a type I transmembrane protein expressed at high prevalence (∼1 x 10*5) and specificity by many carcinomas. We report the results of a Phase I clinical trial of 25 patients with different metastatic cancers (pancreatic, 7; triple-negative breast [TNBC], 4; colorectal [CRC], 3; gastric, 2; small-cell lung [SCLC], 2; esophageal, prostatic, ovarian, non-small-cell lung, renal, tonsillar, urinary bladder, 1 each) after failing a median of 3 prior treatments (some including topoisomerase-I and -II inhibiting drugs). IMMU-132 was administered in repeated 21-day cycles, with each treatment given on days 1 and 8. Dosing started at 8 mg/kg/dose (i.e., 16 mg/kg/cycle), and escalated to 18 mg/kg before encountering dose-limiting neutropenia, in a 3+3 trial design. Fatigue, alopecia, and occasional mild to moderate diarrhea were some of the more common non-hematological toxicities, with 2 patients also reporting a rash. Over 80% of 24 assessable patients had stable disease or tumor shrinkage (17/24 SD; 3/24 PR) among the various metastatic cancers as best response by CT. Three patients (CRC, TNBC, SCLC) have PRs by RECIST; median TTP for all patients, excluding those with pancreatic cancer, is >18 weeks. Neutropenia has been controlled by dose reduction to 8-10 mg/kg/dose (16-20 mg/kg/cycle), which is the Phase II dose. Immunohistochemistry showed strong expression of Trop-2 in most archived patient tumors, but is not detected in serum. Corresponding reductions in blood tumor marker titers (e.g., CEA, CA19-9) reflected tumor responses. No anti-antibody or anti-SN-38 antibodies have been detected despite repeated dosing. Peak and trough assessments of IMMU-132 concentrations in the serum show that the conjugate clears completely within 7 days, an expected finding based on in vitro studies showing 50% of the SN-38 is released in the serum every day. These results indicate that this novel ADC, given in doses ranging from 16-24 mg/kg per cycle, is active in diverse metastatic solid cancers. A Phase II study is ongoing to determine response rates in CRC, TNBC, and SCLC, while also evaluating its potency in other tumor types. Citation Format: Alexander N. Starodub, Allyson J. Ocean, Manish A. Shah, Linda T. Vahdat, Ellen Chuang, Michael J. Guarino, Vincent J. Picozzi, Sajeve S. Thomas, Pius P. Maliakal, Serengulam V. Govindan, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT206. doi:10.1158/1538-7445.AM2014-CT206

Abstract CT236: Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results

Background: Sacituzumab govitecan (IMMU-132) is a new ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 antibody. In vitro and in vivo preclinical data suggest that IMMU-132 is a unique ADC, being most efficacious at a high drug-antibody ratio (DAR) of 7.6, and capable of delivering up to 135-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. In vitro studies also demonstrate specific double-stranded DNA breaks by the internalizing ADC. Methods: IMMU-132 is completing a phase I/II clinical trial with phase II expansion after MTD determination (ClinicalTrials.gov.NCT01631552) in patients with advanced cancers that typically express high levels of Trop-2, at doses of 8 and 10 mg/kg on days 1 and 8 of 21-day repeated cycles. Efficacy (N = 91) and safety (N = 130) results are provided. Results: The% of grades 3/4 AEs for both dose levels are neutropenia (16/4), febrile neutropenia (4/4), anemia (4/0), diarrhea (4/0), and fatigue (4/0) (Table 1). No patient discontinued therapy due to toxicity, and no patient showed immunogenicity despite repeated therapy. Patient dose reductions were 15-16%, and dose delays after first 2 cycles were 3-4%. Conclusions: IMMU-132 shows activity in patients with diverse cancers, even when they no longer responded to a topoisomerase inhibitor. It appears to have a manageable toxicity profile, with promising efficacy at a high therapeutic index in patients with heavily-pretreated metastatic cancers, especially TNBC, SCLC, and NSCLC. Based on these results, this ADC carrying a moderately-toxic drug that is the active metabolite of a currently-used camptothecin analogue represents a novel cancer therapeutic that challenges the current dogma of requiring ultratoxic drugs conjugated at low DARs for ADC therapy. Citation Format: Alexander N. Starodub, Allyson J. Ocean, Aditya Bardia, Michael J. Guarino, Wells Messersmith, Jordan Berlin, Vincent J. Picozzi, Sajeve S. Thomas, Gregory Masters, Linda T. Vahdat, Ingrid A. Mayer, Rebecca Moroose, Jennifer S. Diamond, Scott T. Tagawa, Manish A. Shah, Francois Wilhelm, William A. Wegener, Pius Maliakal, Robert M. Sharkey, David M. Goldenberg. Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT236. doi:10.1158/1538-7445.AM2015-CT236

Abstract CT211: IMMU-130, an SN-38 antibody-drug conjugate (ADC) targeting CEACAM5, is therapeutically active in metastatic colorectal cancer (mCRC): Initial clinical results of two Phase I studies

IMMU-130, an ADC of the active metabolite of CPT-11, SN-38, conjugated by a pH-sensitive linker (7.6 average drug-antibody ratio) to the humanized anti-CEACAM5 antibody (labetuzumab), is completing two Phase I trials. In both, eligible patients with advanced mCRC were required to have failed/relapsed standard treatments, one being the topoisomerase-I inhibiting drug, CPT-11 (irinotecan), and an elevated plasma CEA (>5 ng/mL). IMMU-130 was administered every 14 days (EOW) at doses starting from 2.0 mg/kg in the first protocol (IMMU-130-01). Febrile neutropenia occurred in 2 of 3 patients at 24 mg/kg; otherwise at ≤16 mg/kg, neutropenia (≥ Grade 2) was observed in 7 patients, with one also experiencing thrombocytopenia. One patient [of 8 who received > 4 doses (2 cycles)] showed a 40.6% decrease in liver (starting at 7 cm) and lung target lesions (PR by RECIST) for 4.7 months, with no major toxicity, tolerating a total of 18 doses at 16 mg/kg. The study is continuing at 12 mg/kg EOW. Since SN-38 is most effective in S-phase cells, a more protracted exposure could improve efficacy. Thus, in a second Phase I trial (IMMU-130-02), dosing was intensified to twice-weekly, starting at 6 mg/kg/dose for 2 weeks (4 doses) with 1 week off, as a treatment cycle, in a 3+3 trial design. Neutropenia and manageable diarrhea were the major side effects, until dose reduction to 4.0 mg/kg twice-weekly, with early results indicating multiple cycles are well-tolerated. Currently, tumor shrinkage occurred in 3 patients, with 1 in continuing PR (-46%) by RECIST, among 6 patients who completed >4 doses (1 cycle). In both trials, CEA blood titers correlated with tumor response, and high levels did not interfere with therapy. There have been no anti-antibody or anti-SN-38 antibody reactions, based on ELISA tests. In each study, the ADC was cleared by 50% within the first 24 h, which is much longer exposure than with typical doses of the parental molecule, CPT-11. These results indicate that this novel ADC, given in different regimens averaging ∼16-24 mg/kg/cycle, shows therapeutic activity in advanced mCRC patients. Since CEACAM5 has elevated expression in breast and lung cancers, as well as other epithelial tumors, it may be a useful target in other cancers as well. A Phase II trial evaluating twice-weekly dosing and a new regimen, once-weekly x 2 every 21 days, is ongoing in mCRC. Citation Format: Neil H. Segal, Efrat Dotan, Jordan D. Berlin, Alexander N. Starodub, Michael J. Guarino, Leonard B. Saltz, Pius P. Maliakal, Serengulam V. Govindan, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. IMMU-130, an SN-38 antibody-drug conjugate (ADC) targeting CEACAM5, is therapeutically active in metastatic colorectal cancer (mCRC): Initial clinical results of two Phase I studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT211. doi:10.1158/1538-7445.AM2014-CT211

Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver

Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre-clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg(-1), 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 μM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.

Abstract LB-159: A Phase I study of IMMU-130 (labetuzumab-SN38) anti-CEACAM5 antibody-drug conjugate (ADC) in patients with metastatic colorectal cancer (mCRC).

Background: IMMU-130 is an ADC comprising the humanized monoclonal IgG antibody (mAb), hMN-14 (labetuzumab), bound to the active metabolite of irinotecan, SN-38 (6 SN-38/IgG). hMN-14 a slowly-internalizing mAb, recognizes the CEA (CEACAM5; CD66e) antigen, which is expressed in many solid cancers, including >80% of CRC. hMN-14 was safe in prior clinical trials, when administered unconjugated or bound to 131-I for radioimmunotherapy. In vitro studies showed that the antibody-drug linkage was susceptible to cleavage in serum, with 50% of SN-38 released in ~1.0 day. This means that after the antibody binds to its tumor target, SN-38 is released, leading to a locally enhanced concentration within the tumor site. Irinotecan is a standard therapy of mCRC, but has major gastrointestinal and hematologic toxicity. By targeting SN-38 directly to CEA-expressing tumors, delivery of SN-38 may be increased while avoiding systemic toxicity. In animal CRC xenograft models, IMMU-130 exhibited high anti-tumor activity. A safe starting dose for humans was determined from preclinical toxicology studies that showed no gastrointestinal toxicity, and only transient mild myelosuppression. This single-arm, open-label, dose-escalation, phase I study was undertaken to define the maximum-tolerated dose (MTD) of IMMU-130 in patients with mCRC. Methods: Eligible patients were previously treated with at least one prior irinotecan-containing regimen, had serum CEA >5 ng/mL, and measurable disease by CT/MRI. IMMU-130 was administered every-other-week, with a goal of achieving 12 cycles (24 weeks) in the absence of unacceptable toxicity or disease progression. Pts were entered in cohorts treated at increasing dose levels, with DLT defined as Grade 4 neutropenia ≥ 5 days, ≥ Grade 3 thrombocytopenia, Grade 3 anemia, ≥Grade 3 nausea, vomiting or diarrhea persisting >48 hr, and other ≥ Grade 3 non-hematologic toxicity during the first two cycles. Results: So far 9 pts have been treated at the 2, 4, 8, and 16 mg/kg dose levels. Pts had received a median of 2 prior regimens. The median number of cycles given is 3.9, with 6/9 patients receiving 3 or more doses. Of 5 pts having >2 doses of 16 mg/kg, one has currently received 14 doses and has a continuing partial response after 8. One DLT was observed at 16 mg/kg: Grade 3 thrombocytopenia. The same pt experienced Grade 4 neutropenia Citation Format: Neil H. Segal, Jaclyn Verghis, Serengulam Govindan, Pius Maliakal, Robert M. Sharkey, William A. Wegener, David M. Goldenberg, Leonard B. Saltz. A Phase I study of IMMU-130 (labetuzumab-SN38) anti-CEACAM5 antibody-drug conjugate (ADC) in patients with metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-159. doi:10.1158/1538-7445.AM2013-LB-159

Abstract CT155: Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC)

Introduction: Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) delivering SN-38, a topoisomerase-1 inhibitor, to mSCLC cells expressing Trop-2. We are studying the safety/tolerability and efficacy of IMMU-132 in patients with relapsed/refractory mSCLC who had received a platinum-containing first-line regimen. Experimental Procedure: Patients received 8 or 10 mg/kg IV IMMU-132 on days 1 and 8 of repeated 21-day cycles. Objective tumor response (ORR) was determined by RECISTv1.1 in patients receiving at least one treatment cycle, and progression-free survival (PFS) and overall survival (OS) in all patients by Kaplan-Meier methods. (ClinicalTrials.gov, NCT01631552) Summary of New Unpublished Data: A total of 53 patients (23/30 M/F, median 63 years old) with 1-7 (median 2) prior lines of therapy were enrolled between November, 2013 and June, 2016. Immunohistochemistry of evaluable archival tumor specimens for Trop-2 expression (N=26) showed 92% positivity (61% moderately to strongly positive). They received up to 32 treatment cycles (median 5); the most frequent Grade >3 adverse events were neutropenia (34%), fatigue (13%) and diarrhea (9%). Four patients did not complete one cycle of treatment. In the other 49 patients (14 at 8 mg/kg, 35 at 10 mg/kg), there were 7 confirmed PRs and 21 SDs as best response. The resulting ORR rate was 14% (7/49), with a median duration and time-to-progression of a response of 4.0 and 7.6 mos, respectively, and the clinical benefit rate (PR+SD >4 mos) was 35% (17/49). The ORR rate was similar in pts who were sensitive (>3 mos response) or resistant ( Conclusion: These interim results demonstrate encouraging activity in patients with late-stage mSCLC having a high expression of Trop-2. Even after failing 1st-line platinum chemotherapy or 2nd-line topotecan therapy, IMMU-132 showed promising activity, and has a manageable toxicity profile. IMMU-132 given at 10 mg/kg on day 1 and 8 of a 3-week cycle was selected for further clinical evaluation in this population. Citation Format: Jhanelle E. Gray, Rebecca S. Heist, Alexander N. Starodub, D. Ross Camidge, Ebenezer Kio, Gregory Masters, W. Thomas Purcell, Michael J. Guarino, Jamal Misleh, Charles J. Schneider, Bryan J. Schneider, Allyson J. Ocean, Tirrell Johnson, Leena Gandhi, Kevin Kalinsky, Serengulam V. Govindan, Pius Maliakal, Boyd Mudenda, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT155. doi:10.1158/1538-7445.AM2017-CT155

Abstract LB-C16: Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:30 PM ET Sunday, November 8. Citation Format: Aditya Bardia, Ingrid Mayer, Jennifer Diamond, Alexander Starodub, Rebecca Moroose, Steven Isakoff, Allyson Ocean, Michael Guarino, Kevin Kalinsky, Joyce O9Shaugnessy, Francois Wilhelm, Pius Maliakal, Robert Sharkey, David Goldenberg, Linda Vahdat. Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C16.

Abstract P5-19-27: IMMU-132, a new antibody-drug conjugate (ADC) against Trop-2, as a novel therapeutic for patients with relapsed/refractory, metastatic, triple-negative breast cancer (TNBC): Results from Phase I/II clinical trial (NCT01631552)

Background: TNBC, comprising 15-20% of all invasive breast cancers, represents an aggressive phenotype with high risk of recurrence and mortality. Trop-2 is a cell-surface glycoprotein expressed on many human carcinomas, including TNBC. High Trop-2 expression is associated with more aggressive disease and poor prognosis in several cancers, including breast cancer. We report interim results from a Phase I/II trial evaluating a novel ADC, IMMU-132 (isactuzumab govitecan), comprising a humanized anti-Trop-2 antibody conjugated to the topoisomerase I inhibitor, SN-38 (active metabolite of irinotecan). The drug:antibody ratio of 7.6 facilitates the delivery of high-dose chemotherapy preferentially to the tumor cells. Methods: Patients (pts) with relapsed/refractory metastatic epithelial tumors were enrolled at escalating IMMU-132 doses (8 to 18 mg/kg), given on days 1 and 8 of a 21-day cycle. The Phase II dose at this schedule was 10 mg/kg. CT scans were performed every 6-8 weeks to assess response using RECIST 1.1. During the dose-escalation portion, evidence of antitumor activity, including 3 partial responses (TNBC, small-cell lung cancer and colorectal cancer) and many with durable stable disease (SD), was observed, leading to Phase II expansion. Results: As of Sept. 25, 2014, a total of 132 pts have been enrolled, including 30 with advanced/metastatic TNBC. Currently evaluable TNBC pts (N=17) had a median age of 50 (33-77), with a median of 4 prior drug regimens (range 1-8), and 67% having received prior platinum-containing regimens. In this heavily pre-treated population, there were 4 PRs (25%) and 9 SDs (56.3%) per RECIST v1.1, representing a disease control (PR+SD g 4 mos) of 53% among evaluable pts with adequate follow-up. A maximum shrinkage of target lesions of 33%, 44%, 51%, and 60% for pts with PRs, and 14%, 19%, and 27% for 3 pts with SD, was determined. Biomarker CA15.3 directional changes correlated with RECIST. All but one pathology specimen were Trop-2+ by immunohistochemistry. HPLC analysis of serum samples found l5% unbound SN-38. The half-life of IMMU-132 was 23 h, which is similar to the predicted half-life from in vitro serum stability studies. Grade 3/4 toxicities were: neutropenia (G3, 4 pts, 23.5%) with 1 febrile neutropenia (5.9%), and lymphocytopenia (1 Gr 3, 1 pt, 5.9%). Grade 1/2 events were fatigue (35.3%), diarrhea (41.2%), and alopecia (29.4%). No pt discontinued therapy due to toxicity. Conclusions: Based on laboratory and initial clinical results, IMMU-132 is an ADC that selectively delivers a topoisomerase I inhibitor to cancer cells without the need for enrichment by a companion diagnostic. It is safe, well-tolerated, with preliminary evidence of encouraging efficacy in heavily-pretreated pts with relapsed/refractory metastatic TNBC. Randomized Phase III and combination trials are being planned. Citation Format: Aditya Bardia, Alexander Starodub, Rebecca L Moroose, Ingrid A Mayer, Jennifer R Diamond, Ellen Chuang, Serengulam V Govindan, Robert M Sharkey, Pius Maliakal, William A Wegener, Steven A Hamburger, Allyson J Ocean, David M Goldenberg, Linda T Vahdat. IMMU-132, a new antibody-drug conjugate (ADC) against Trop-2, as a novel therapeutic for patients with relapsed/refractory, metastatic, triple-negative breast cancer (TNBC): Results from Phase I/II clinical trial (NCT01631552) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-27.