On December 6, 2016 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported updated safety and efficacy data from an ongoing phase 1/2a clinical study evaluating MOR202 alone and in combination with immunomodulatory drugs (IMiDs) lenalidomide (Len) and pomalidomide (Pom), plus dexamethasone (Dex), in heavily pre-treated patients with relapsed/refractory multiple myeloma (MM) (Press release, MorphoSys, DEC 5, 2016, View Source [SID1234516958]). MOR202 is an investigational human antibody targeting CD38 . Data were presented during an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California/USA.

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"The results presented include updated data from higher dosing cohorts of MOR202 in combination with IMiDs, in patients being evaluable for efficacy and safety assessment. In addition to the infusion time of 2 hours and the occurrence of infusion-related reactions in only 7% of the patients, we are particularly pleased with the responses seen in patients treated with MOR202 plus Len/Dex and Pom/Dex", Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG, commented. "We look forward to enrolling more patients in the highest dosing cohorts of 16 mg/kg MOR202 in these combinations."

Patients treated with MOR202 in combination with Len/Dex had a median of 2 prior regimens; 64% were refractory to their last therapy. In this arm of the trial, 91% of evaluable patients (10 out of 11) showed an objective response (defined as either a complete response (CR) or a partial response (PR)) to MOR202 and Len/Dex. Considering only patients in the highest dosing cohort of 16mg/kg MOR202 plus Len, ORR (objective response rate) was 100%, with 7 out of 7 patients showing response to treatment.

In the group receiving MOR202 with Pom/Dex, patients had a median of 3 prior therapies, all being refractory to their last therapy. In these heavily pretreated patients, 57% (4 out of 7) showed a response, with two patients achieving a complete remission (CR). In relapsed/refractory patients treated with MOR202 alone, 29% (5 out of 17) showed an objective response.

Responses are ongoing in 16 of 19 patients, with the longest response ongoing for more than 14 months. The median progression-free survival (PFS) of the patients treated with MOR202 alone was 4.7 months; the median PFS for the combination regimen has not yet been reached.

MOR202 was given as a 2-hour infusion up to the highest dose of 16 mg/kg. Infusion-related reactions (IRRs) occurred in 7% of patients and were limited to grade 1 or 2. The most frequent adverse events of grade 3 or higher were lymphopenia, neutropenia and leukopenia. No unexpected safety signals were observed. No treatment-related deaths were reported.

According to a biomarker analysis, CD38 molecules were preserved on bone marrow plasma cells during MOR202 treatment, comparing values at baseline and at cycle 2 day 1.

Number und tittle of the presentation:
Abstract #1152
Raab et al: A Phase I/IIa Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma

MorphoSys held an Investor & Analyst Event at the 2016 ASH (Free ASH Whitepaper) Annual Meeting on December 5, 2016, at 8:00pm PST (December 6, 2016: 4:00am GMT, 5:00am CET). Two clinical investigators presented clinical data for MorphoSys’s investigational agents MOR208 and MOR202.
A replay and the presentation will be made available at View Source
Webcast: View Source

About MOR202 and the ongoing phase 1/2a study in multiple myeloma
The investigational drug MOR202 is a fully human HuCAL antibody targeting CD38, a highly expressed and validated target in multiple myeloma. Data are from an ongoing clinical phase 1/2a, open-label, multi-center, dose-escalation study conducted in several sites in Germany and Austria. The study is evaluating the safety and preliminary efficacy of MOR202 alone and in combination with the immunomodulatory drugs pomalidomide (Pom) and lenalidomide (Len) plus dexamethasone (Dex) in patients with relapsed/refractory multiple myeloma. The primary endpoints of the trial are the safety, tolerability and recommended dose of MOR202 alone and in combination with the IMiDs. Secondary outcome measures are pharmacokinetics and preliminary efficacy based on overall response rate, duration of response, time-to-progression, and progression-free survival.

On December 5, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported updated findings evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in two trials of patients with relapsed or refractory classical Hodgkin lymphoma (cHL) (Press release, Merck & Co, DEC 5, 2016, View Source [SID1234516946]). In the KEYNOTE-087 and KEYNOTE-013 trials, KEYTRUDA demonstrated overall response rates (ORR) of 69.0 percent and 58 percent, respectively. KEYNOTE-013, which had a median follow up of 29 months, showed responses of 12 months or greater in 70 percent of patients who responded to therapy. These findings will be presented today at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper). Additionally, data from these trials supported the recently announced regulatory filing with the U.S. Food and Drug Administration.

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"As the data mature from these two studies, we continue to be encouraged by the response rates, including complete remission and durable responses, in patients with relapsed or refractory classical Hodgkin lymphoma," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories.

The KEYTRUDA clinical development program includes more than 30 tumor types in nearly 400 clinical trials, including more than 200 trials that combine KEYTRUDA with other cancer treatments. For hematologic malignancies specifically, Merck is conducting broad immuno-oncology research assessing the role of monotherapy and combination regimens with KEYTRUDA (pembrolizumab). The hematology program includes nearly 40 ongoing studies – including company sponsored, investigator sponsored and collaborative studies; several of these are registration-enabling trials.

"When patients with classical Hodgkin lymphoma do not respond to standard of care chemotherapy or autologous stem cell transplantation, the cancer is difficult to successfully treat. For these patients, who are often in their 20s and 30s, the need to identify new treatment options is urgent," said Dr. Craig Moskowitz, clinical director, division of hematologic oncology, Memorial Sloan Kettering Cancer Center. "These data are promising and show that pembrolizumab may provide meaningful clinical benefit to patients with this disease."

Results from KEYNOTE-087

Results from the KEYNOTE-087 trial will be presented in an oral presentation by Dr. Moskowitz at 5 p.m. PST (Location: San Diego Convention Center, Room 6B) (Abstract #1107).

KEYNOTE-087 is a multicenter, open-label, multi-cohort, activity-estimating phase 2 trial evaluating KEYTRUDA (200 mg fixed dose every three weeks) monotherapy in patients with relapsed or refractory cHL across three cohorts. The primary endpoints include overall safety, tolerability, and ORR (per blinded independent central review, BICR); secondary endpoints include ORR (per investigator review), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The patient cohorts are intended to assess the outcome measures in: patients whose disease progressed following an autologous stem cell transplantation and subsequent treatment with brentuximab vedotin, an antibody drug conjugate (Cohort 1); patients who failed salvage chemotherapy and were ineligible for a transplant and whose disease progressed following treatment with brentuximab vedotin (Cohort 2); and patients whose disease progressed after transplant and who did not receive brentuximab vedotin after transplant (Cohort 3).

Across all 210 enrolled patients, the ORR was 69.0 percent (n=145; 95% CI, 62.3-75.2) by BICR, and the complete remission rate was 22.4 percent (n=47; 95% CI, 16.9-28.6). Across all cohorts, 93 percent of patients experienced a decrease in tumor burden (n=192).

By cohort, the data showed:

In Cohort 1, (n=69), ORR was 73.9 percent (n=51; 95% CI, 61.9-83.7) – with complete remissions in 21.7 percent (n=15; 95% CI, 12.7-33.3) and partial remissions in 52.2 percent (n=36; 95% CI, 39.8-64.4) of patients. An additional 15.9 percent of patients had stable disease (n=11; 95% CI, 8.2-26.7) and 7.2 percent of patients had progressive disease (n=5; 95% CI, 2.4-16.1). Additionally, 82.2 percent of responding patients had a response of six months or greater.
In Cohort 2 (n=81), ORR was 64.2 percent (n=52; 95% CI, 52.8-74.6) – with complete remissions in 24.7 percent (n=20; 95% CI, 15.8-35.5) and partial remissions in 39.5 percent (n=32; 95% CI, 28.8-51.0) of patients. An additional 12.3 percent of patients had stable disease (n=10; 95% CI, 6.1-21.5) and 21.0 percent of patients had progressive disease (n=17; 95% CI, 12.7-31.5). Additionally, 70 percent of responding patients had a response of six months or greater.
In Cohort 3 (n=60), ORR was 70.0 percent (n=42; 95% CI, 56.8-81.2) – with complete remissions in 20.0 percent (n=12; 95% CI, 10.8-32.3) and partial remissions in 50.0 percent (n=30; 95% CI, 36.8-63.2) of patients. An additional 16.7 percent of patients had stable disease (n=10; 95% CI, 8.3-28.5) and 13.3 percent of patients had progressive disease (n=8; 95% CI, 5.9-24.6). Additionally, 75.6 percent of responding patients had a response of six months or greater.
Results also included an analysis of patients with primary refractory disease (n=73), defined as failure to achieve complete or partial response to first-line treatment. In this patient population, the ORR (per BICR) was 79.5 percent (n=58; 95% CI, 68.4-88.0). Additionally, an ORR of 67.8 percent (95% CI, 59.6-75.3) was reported in patients who relapsed after three or more lines of prior therapy (n=99/146).

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported studies. The most common treatment-related adverse events were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%) and neutropenia (5.2%). The most common grade 3 or 4 treatment-related adverse events were neutropenia (2.4%), diarrhea (1.0%) and dyspnea (1.0%). Immune-mediated adverse events included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%) and myositis (1.0%). There were nine discontinuations because of treatment-related adverse events and no treatment-related deaths.

Results from KEYNOTE-013

Results from the KEYNOTE-013 trial will be presented in an oral presentation by Dr. Philippe Armand, medical oncologist, Dana-Farber Cancer Institute at 5:15 p.m. PST (Location: San Diego Convention Center, Room 6B) (Abstract #1108).

KEYNOTE-013 is an ongoing, multicenter, non-randomized, phase 1b trial of approximately 200 patients evaluating the safety, tolerability, and efficacy of KEYTRUDA (pembrolizumab) monotherapy in patients with blood cancers, including myelodysplastic syndromes, multiple myeloma, classical Hodgkin lymphoma, mediastinal large B cell lymphoma and certain other non-Hodgkin’s lymphoma (or lymphomata). The primary endpoints of the study include overall safety, tolerability, and complete remission rate (as measured by International Harmonization Project Response Criteria); secondary endpoints include ORR, DOR, PFS, and OS.

Data from a cohort of the study evaluated KEYTRUDA monotherapy at 10 mg/kg every two weeks in patients with relapsed or refractory cHL who had progressed on or after treatment with brentuximab vedotin after failure of autologous stem cell transplant, or who were transplant-ineligible. Response was assessed at week 12 and every 8 weeks thereafter according to the International Harmonization Project 2007 criteria.

Across all 31 patients enrolled in the KEYNOTE-013 classical Hodgkin lymphoma cohort, the ORR was 58 percent (n=18; 95% CI, 39-76) by BICR, and the complete remission rate was 19 percent (n=6; 95% CI, 8-38). Thirty-nine percent of patients achieved partial remission (n=12; 95% CI, 22-58) and 23 percent had stable disease (n=7; 95% CI, 10-41). The median duration of response was not yet reached (range 0.0+ to 26.1+ months) and 70 percent of responding patients had a response of 12 months or greater. The median duration of follow-up was 29 months.

Measured by BICR, median PFS was 11.4 months (4.9-27.8). The six-month PFS rate was 66 percent and the 12-month rate was 48 percent. Median OS was not reached. Six-month and 12-month OS rates were 100 percent and 87 percent, respectively.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. The most common treatment-related adverse events were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%) and dyspnea (10%). The most common grade 3 or 4 treatment-related adverse events were colitis (3%), axillary pain (3%), AST increased (3%), joint swelling (3%), nephrotic syndrome back pain (3%) and dyspnea (3%). Adverse events leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2) and pneumonitis (grade 2). There were no treatment-related deaths.

About Hodgkin Lymphoma

Hodgkin lymphoma is a type of lymphoma that develops in the white blood cells, called lymphocytes, which are part of the immune system. Hodgkin lymphoma can start almost anywhere – most often in lymph nodes in the upper part of the body, with the most common sites being in the chest, neck or under the arms. In 2016, it is estimated that more than 8,500 people will be diagnosed with Hodgkin lymphoma in the U.S.; cHL accounts for about 95 percent of all cases of Hodgkin lymphoma in developed countries.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA (pembrolizumab) is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA (pembrolizumab) can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA (pembrolizumab) can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA (pembrolizumab) was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes nearly 400 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On December 5, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported preliminary safety and efficacy data from a phase 1 study of DS-3032, an investigational oral selective MDM2 inhibitor, suggesting that DS-3032 may be a promising treatment for hematological malignancies including relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) (Press release, Daiichi Sankyo, DEC 5, 2016, View Source [SID1234516945]). Preliminary results from the dose esclation part of the phase 1 study of DS-3032 were presented in an oral presentation at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

A total of 38 patients with relapsed/refractory AML or high-risk MDS were enrolled into the study. Five dose levels of DS-3032 (60 mg, 90 mg, 120 mg, 160 mg and 210 mg) were given. The maximum tolerated dose of DS-3032 was determined to be 160 mg once daily for 21 days in a 28 day cycle based on results from 37 patients who received at least one dose of DS-3032.

Clinical activity of DS-3032 was observed by a reduction of bone marrow blasts at the end of the first cycle of treatment in 15 out of 26 patients who had at least one post-dose bone marrow evaluation. Complete remission was seen in two patients with relapsed/refractory AML receiving 120 mg and 160 mg of DS-3032 with a duration of approximately four months and 13 months, respectively. One patient with high-risk MDS receiving the 120 mg dose of DS-3032 achieved marrow complete remission with platelet improvement for four months. Each of the three patients experiencing a complete response showed a TP53 gene mutation while receiving treatment, which was not identified at the start of the study.

"MDM2 inhibitors such as DS-3032 represent a promising approach in cancer therapy as they have the potential to restore the tumor suppressor protein function of p53 via release from the inhibitory effects of MDM2. Wild-type p53 plays an important role in preventing the uncontrolled growth of cancer cells," said Courtney DiNardo, MD, MSCE, Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "While these findings are encouraging in that single-agent clinical activity in refractory hematologic malignancies was demonstrated with DS-3032, further study with optimized dosing regimens including combination strategies is needed."

Five patients experienced dose limiting toxicities including two patients in the 160 mg cohort (grade 3 hypokalemia and diarrhea) and three patients in the 210 mg cohort (grade 3 nausea/vomiting, grade 3 anorexia/fatigue and grade 2 creatinine elevation/renal insufficiency leading to early discontinuation of treatment). The most common treatment-emergent adverse events (TEAEs) of any grade (greater than 20 percent) included nausea (73 percent), diarrhea (57 percent), vomiting (33 percent), fatigue (37 percent), anemia (33 percent), thrombocytopenia (33 percent), neutropenia (20 percent), hypotension (30 percent), hypokalemia (23 percent), and hypomagnesemia (20 percent).

"Additional research is currently underway to further explore the appropriate dose and treatment schedule of DS-3032 as well as determine how it can be combined with other therapies," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "We are committed to investigating novel approaches to treat AML and MDS in hopes of changing the standard of care for these patients."

About the Study
The primary objectives of the dose escalation part of the phase l study are to assess the safety, tolerability, and maximum tolerated dose or the tentative recommended phase 2 dose of DS-3032 in several hematological malignancies including refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myleoid leukemia (CML) in blast phase, and myelodysplastic syndrome (MDS). Secondary objectives include evaluating the pharmacokinetics and pharmacodynamic effects of DS-3032. Exploratory objectives include evaluating the efficacy of DS-3032. Further evaluation of alternative dosing schedules of DS-3032 is currently underway. For more information about the study visit ClinicalTrials.gov.

About DS-3032
DS-3032 is an investigational oral selective inhibitor of the murine double minute 2 (MDM2) protein currently being investigated in three phase 1 clinical trials for solid and hematological malignancies including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma and myelodysplastic syndrome (MDS). DS-3032 has not been approved by any regulatory authority for uses under investigation.

MDM2 is a ubiquitously expressed protein that plays an important role in tissue development and tightly regulates p53, a protein that functions as a tumor suppressor.1 Overexpression or oncogenic activation of MDM2 can disrupt the balanced MDM2 and p53 interaction, blocking the tumor suppressor activity and leading to solid tumors and hematological malignancies.1,2 Small molecules designed to block the MDM2-p53 interaction, reactivating p53 to suppress tumors, may be a promising therapeutic approach for the treatment of wild-type (non-mutant) p53 cancer.1

Unmet Need in AML and MDS
Acute myeloid leukemia (AML) is the most common type of acute leukemia, accounting for about 33 percent of all new cases of leukemia.3 The five-year survival rate of AML is approximately 26 percent, which is the lowest of all leukemias.3 In the U.S., each year there are about 13,000 new cases of myelodysplastic syndrome (MDS), a type of cancer that can occur when the blood-forming cells in the bone marrow are damaged.4 In about one in three patients, MDS progresses to AML.4 Currently, there are no approved targeted treatments for AML, with little progress in approval of new drugs for AML over the past 30 years.5,6

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Discover why more than 1,500 members use 1stOncology™ to excel in:

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On December 5, 2016 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported a review of results to date from its multicenter BP-004 clinical trial of BPX-501 in the pediatric setting, and provided an update on the regulatory pathway for product registration in Europe at an investor and analyst event held today (Press release, Bellicum Pharmaceuticals, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227672 [SID1234516942]). Clinical results on BPX-501 in children with hematological malignancies were also presented in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting.

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"We have made significant progress with our BPX-501 program since initiating the BP-004 clinical trial in children two years ago," commented Tom Farrell, President and CEO of Bellicum Pharmaceuticals. "To date, we have treated more than 100 patients at leading pediatric transplant centers in Europe and the U.S. Results thus far have been impressive—including GvHD- and disease-free outcomes in children with a range of blood cancers and genetic diseases, as reported this weekend in several presentations at ASH (Free ASH Whitepaper). We’re also pleased with the progress we’ve made in formalizing an expedient pathway to regulatory approval in Europe with BPX-501 to treat both malignant and nonmalignant diseases. We look forward to providing an update on our U.S. regulatory path in the first half of 2017."

Overall Summary of Results of BP-004 Study with BPX-501 (n=85)

The Company presented a review of results to date of the BP-004 study in pediatric patients with malignant and nonmalignant diseases who underwent a haploidentical hematopoietic stem cell transplant (HSCT) followed by an add-back of genetically modified BPX-501 T cells. Eighty-five patients have been treated with BPX-501 at multiple U.S. and European sites and followed for at least 100 days (out of a total of 105 patients treated to date). Only one case of transplant-related mortality has been reported, unrelated to BPX-501 cells, and none out of 51 patients with nonmalignant disorders. Compared to T-depleted haplo-transplants alone, results have also shown significantly faster immune recoveries, as well as reduced viral infections and reactivation, and reductions in time to hospital discharge and re-hospitalizations due to infection. In five cases where uncontrolled acute GvHD was attributable to BPX-501 cells, rimiducid was administered and symptoms resolved.

Results have been consistent across a range of diseases and disorders where allogeneic HSCT is recognized as curative, including hemoglobinopathies such as Beta Thalassemia Major (β0β0), Sickle Cell Disease and Diamond-Blackfan Anemia; Primary Immune Deficiencies such as Severe Combined Immune Deficiency ("Bubble boy" disease) and Wiskott-Aldrich syndrome; leukemias and lymphomas; and bone marrow failure syndromes. The Company also reported that of six refractory AML patients treated under compassionate use because of their active disease and not included in the BP-004 summary data, 4 remain alive and in remission, including two who are now 11 and 20 months post-transplant.

Regulatory Update for BPX-501 in the European Union

The Company also announced today that the protocol assistance provided by the European Medicines Agency (EMA) for the registration study of BPX-501 in Europe is complete, and the Company is finalizing plans for the BP-004 trial extension. The Company will continue enrolling up to 40 additional patients with malignant and nonmalignant diseases in the trial. Concurrent with this study, the Company will initiate a comparator trial of malignant and nonmalignant patients receiving a matched unrelated donor (MUD) HSCT. This trial will include both retrospective patients and up to 40 prospective patients. The primary endpoint will be event-free survival (death, GvHD and infection) at 6 months.

Bellicum anticipates that it could pursue approval in the EU under the "exceptional circumstances" provision. Exceptional circumstances may be granted for medicines that treat very rare diseases, or where controlled studies are impractical or not consistent with accepted principles of medical ethics. The Company continues to discuss the regulatory path to approval in the U.S. with FDA and expects to provide an update in the first half of 2017.

Also today at the ASH (Free ASH Whitepaper) 2016 annual meeting, updated results were presented in patients with acute myeloid leukemia (AML).

AML Highlights (Abstract #4683)

"T-cell depleted HLA-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) followed by donor lymphocyte infusion with T cells transduced with the inducible caspase 9 (iC9) suicide gene in children with hematological malignancies"

In a poster session, investigators presented data in 33 children with AML who received an α/β TCR-depleted haplo-HSCT and BPX-501 cells. The data indicate that infusion of BPX-501 results in low non-relapse mortality, and low rates of acute and chronic Graft versus Host Disease. Median follow-up was 8 months (range: 1–19 months). All 33 patients were high-risk CR1 (6/33) or CR2 (27/33). Study outcomes include:

All 33 patients engrafted with no secondary graft failure
One patient with steroid-resistant Grade II skin acute GvHD received rimiducid with complete resolution of disease in 24 hours
One treatment-related mortality from chronic GvHD was determined to be allograft-related and not from BPX-501 T cells
3 of 33 patients have relapsed; the probability of disease-free survival at 15 months is 83.6%
A replay of the investor and analyst meeting held today can be accessed from the News & Events section of the Bellicum website. An archived version of the webcast will be available for at least two weeks following the event.

About BPX-501

BPX-501 is an adjunct T-cell therapy administered after allogeneic HSCT, comprising genetically modified donor T cells incorporating Bellicum’s CaspaCIDe safety switch. It is designed to provide a safety net to eliminate alloreactive BPX-501 T cells (via administration of activator agent rimiducid) should uncontrollable GvHD occur. This enables physicians to more safely perform stem cell transplants by adding back BPX-501 engineered T cells to speed immune reconstitution and provide control over viral infections, without unacceptable risk of uncontrollable GvHD. The ongoing BP-004 Phase 1/2 clinical study of BPX-501 is being conducted at transplant centers in the U.S. and Europe.

On December 5, 2016 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO) reported new clinical data from the ongoing Phase 1 study evaluating single agent AG-120 in advanced hematologic malignancies at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) (Press release, Agios Pharmaceuticals, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227727 [SID1234516941]). AG-120 is a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1).

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As of August 1, 2016, data from the completed dose-escalation portion of the Phase 1 trial from 78 patients with advanced IDH1 mutant positive hematologic malignancies treated with AG-120, including 63 patients with relapsed and/or refractory (R/R) acute myeloid leukemia (AML), continue to show a favorable safety profile and durable clinical activity. Data from the ongoing expansion phases were not reported. For all dose escalation patients, an overall response rate of 38% (30 of 78) and a complete remission rate of 18% (14 of 78) were observed. For the 63 R/R AML patients, the overall response rate and complete remission rates were 33% (21 of 63) and 16% (10 of 63) respectively. Patients were on study treatment for up to 24.2 months with a median duration of response of 10.2 months for all responders and 6.5 months for the R/R AML responding patients.

In order to study the depth of response to single agent AG-120, molecular detection of the mutant IDH1 burden in blood and bone marrow samples (collected at pre-treatment and at least one on-treatment time point) were analyzed using next generation sequencing (NGS, FoundationOne Heme assay) in 67 patients from the dose-escalation portion of the study. Molecular clearance was defined as reduction of the IDH1 mutation below the limit of detection of the assay (1% for IDH). Molecular data show that treatment with AG-120 resulted in clearance of the IDH1 mutation in 36% of patients (5 of 14) in complete remission compared to 4% of patients (2 of 53) that did not achieve complete remission (p-value=0.003). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance.

"AG-120 continues to demonstrate an impressive single-agent efficacy and safety profile in this cohort of high-risk relapsed or refractory AML patients, with some responses maintained for approximately two years," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "In addition, new molecular data for AG-120 suggests some patients experience clearance of the IDH1 mutant gene in their blood or bone marrow as assessed by next generation sequencing, demonstrating the depth of response that can occur with AG-120 therapy."

"We are encouraged by the durable clinical activity of AG-120 and are working to bring this medicine to waiting patients with IDH1 mutant positive AML whose disease has progressed after standard treatments," said Chris Bowden, M.D., chief medical officer of Agios. "We plan to explore a similar expedited regulatory strategy for AG-120 that is being utilized for enasidenib (AG-221), which could result in an NDA submission in 2017."

Updated Phase 1 Dose-Escalation Data for AG-120 in Advanced Hematologic Malignancies

Clinical and molecular data reported are from 78 patients treated with AG-120 in the dose escalation phase of the ongoing Phase 1; data from the ongoing expansions were not reported. Doses were administered from 200 mg to 1,200 mg total daily doses. As of August 1, 2016, seven patients (9%) remain on treatment. The median age of these patients is 68 (ranging from 36-89). Patients received a median of two prior chemotherapy regimens (ranging from zero to five). A safety and efficacy analysis was conducted for all 78 treated dose-escalation patients. In addition, longitudinal mutant IDH1 (mIDH1) variant allele frequency (VAF) data were available for 67 patients.

Safety Data

A safety analysis conducted for all 78 treated patients as of the data cut-off shows that AG-120 continues to demonstrate a favorable safety profile.

The majority of adverse events reported by investigators were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea, pyrexia and peripheral edema.
Fifty-three patients experienced at least one serious adverse event (SAE), the majority being disease related.
The maximum tolerated dose was not reached. The recommended Phase 2 dose was 500 mg once daily, which is being studied in the ongoing expansion phase of the trial.
Nine patients discontinued from the study due to death, including one reported as possibly related to AG-120.
All cause mortality at 30 and 60 days were 12% and 21%, respectively.
Efficacy Data

Thirty out of 78 treated patients achieved investigator-assessed objective responses for an overall response rate of 38%.

Of the 30 patients who achieved an objective response, there were 14 (18%) complete remissions (CR), eight CRs with incomplete neutrophil recovery or platelet recovery (CRi/CRp), six marrow CR (mCR)/morphologic leukemia-free state (MLFS) and two partial remissions (PR).
Of the 63 patients with R/R AML, 21 (33%) achieved an objective response, including 10 (16%) CRs, eight CRi/CRp, two MLFS and one PR.
Responses were durable, with a median response duration of 10.2 months (3.7- not estimable (NE)) overall and 6.5 months (3.7-NE) in the subset of patients with R/R AML.
Median duration of treatment is 3.2 months (ranging from 0.1 to 24.2 months).
IDH1 Mutational Clearance

Longitudinal mIDH1 VAF data were reported for 67 patients. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having:

mIDH1 detected at screening (any sample type), and
no reported mIDH1 mutation in at least one on-study time point (FoundationOne Heme sensitivity of 1%).
Importantly, IDH1-MC was observed in 36% of CRs (5 of 14) and 4% of non-CRs (2 of 53). IDH1-MC was enriched in patients achieving CR (p-value = .003). The median time to mutational clearance was 2.7 months (ranging from 1.1 to 3.8 months). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance. Agios is continuing to study the potential relationship between IDH1-MC and clinical benefit for patients with AML.

About the Ongoing Phase 1 Trial for AG-120 in Advanced Hematologic Malignancies
AG-120 is being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion arms, including:

Arm 1: 125 IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to initial induction or reinduction treatment, or who relapse within one year of initial treatment, excluding patients with favorable-risk status
Arm 2: 25 untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
Arm 3: 25 patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
Arm 4: 25 patients with relapsed IDH1 mutant positive AML not eligible for arm 1 who have failed or are unable to receive standard of care
About Variant Allele Frequency (VAF)
Sequencing studies have demonstrated that most tumors exhibit extensive intra-tumor genetic heterogeneity characterized by individual cells that have different somatic mutations. For single-nucleotide mutations, or variants, the VAF is defined as the fraction of DNA sequence reads covering the variant position that contains the variant allele. This technique makes it possible to infer the subpopulations of tumor cells by counting the number of DNA sequence reads that contain a specific somatic mutation.

About IDH Mutations and Cancer
IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Immature white blood cells known as myeloblasts, or "blasts" proliferate in the bone marrow rather than mature into normal blood cells. The decrease in normal blood cells can result in severe complications for patients including infections and dependence on blood product transfusions. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. Less than 10 percent of U.S. AML patients are eligible for bone marrow transplant and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 and IDH2 mutations are present in about 15 to 23 percent of AML cases.