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80	80	-Proof of concept 2019
81	81	)))| |Rare disease| |Pediatric clinical trial
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84	84	//Rigosertib IV for higher-risk MDS//
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86	86	Onconova Therapeutics is developing an IV version of rigosertib for the treatment of higher-risk MDS following the failure of HMA therapy. In early 2014, the company announced topline survival results from its “ONTIME” trial, a multi-center Phase 3 clinical trial of rigosertib IV as a single agent versus best supportive care including low dose Ara-C. The ONTIME trial did not meet its primary endpoint of an improvement in overall survival in the intent-to-treat population, although improvements in median overall survival were observed in various pre-specified and exploratory subgroups of higher-risk MDS patients. As a result, a new pivotal trial referred to as INSPIRE is on-going to study what the company believe is a more homogenous population in higher-risk MDS.
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102	102	Onconova Therapeutics is developing rigosertib oral for use in combination with azacitidine prior to treatment with HMA therapy for higher risk MDS. In December 2016, at the American Society of Hematology (ASH) Annual Meeting and in June 2017, at the Congress of the European Hematology Association Meeting (EHA), the company presented Phase 1/2 data from the initial portion of an ongoing rigosertib oral and azacitidine combination trial in higher-risk MDS. 33 of 40 MDS patients enrolled were evaluable for response at the time of the analysis. The median age of patients was 66, with 73% being male. The IPSS-R distribution was: 7.5% Low, 12.5% Intermediate, 37.5% High, 32.5% Very High and 10% unknown. 76% of patients responded per 2006 International Working Group (IWG) criteria. Responses were as follows:
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	104	+|** **|** **|**Overall
	105	+Evaluable
	106	+(N=33)**|** **|**No prior
	107	+HMA
	108	+(N-20)**|** **|**Prior
	109	+HMA
	110	+(N=13)**|** **
	111	+|Complete remission (CR)| |8(24|)%|7(35|)%|1(8|)%
	112	+|Marrow CR + hematologic improvement| |10(30|)%|6(30|)%|4(31|)%
	113	+|Marrow CR alone| |6(18|)%|3(15|)%|3(23|)%
	114	+|Hematologic improvement alone| |1(3|)%|1(5|)%|0|
	115	+|Stable disease| |8(24|)%|3(15|)%|5(38|)%
	116	+|Overall IWG response| |25(76|)%|17(85|)%|8(62|)%
	117	+|Clinical benefit response| |19(58|)%|14(70|)%|5(38|)%
105	105
106		-
107	107	The median duration of response was 8 months for CR, 12.3 months for marrow CR.
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	122	+//Safety/Tolerability of the Combination~://
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111		-
112		-Safety/Tolerability of the Combination:
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117	117	Based upon a comprehensive analysis of patients receiving oral rigosertib in combination with azacitidine that was presented in 2016, the combination of rigosertib oral and azacitidine was well tolerated. The most common TEAEs in > 10% of patients with MDS/AML (n=54) receiving rigosertib oral and azacitidine were nausea (41%), fatigue (39%), diarrhea (37%), constipation (37%) and dysuria (28%). The most common serious AEs were pneumonia (11%) and febrile neutropenia (7%). The most common AEs leading to discontinuation were AML (4%) and pneumonia (4%).
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	126	+//Next steps for rigosertib oral in combination with azacitidine for higher-risk MDS//
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121		-
122		-Next steps for rigosertib oral in combination with azacitidine for higher-risk MDS
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124		-
125		-
126		-
127	127	Following an end of Phase 2 meeting with the Food and Drug Administration (FDA) in September 2016, the company began development of a Phase 3 protocol. The Phase 3 trial will be designed as a global 1:1 randomized, placebo-controlled trial of rigosertib oral plus azacitidine compared to azacitidine plus oral placebo. Based on the results of the Phase 1/2 Study, a full dose of azacitidine will be used in combination with rigosertib oral, as defined in the product insert for azacitidine. The patient population studied in this proposed trial will be first-line (HMA naïve) higher-risk MDS patients. The primary endpoint for assessment of efficacy will be the composite Response Rate of complete remission (CR) + partial remission (PR,) as per the IWG 2006 Response Criteria. The trial will be under the review of a DMC. Formal FDA review may be sought via the Special Protocol Assessment (SPA) mechanism. The company will not commence the Phase 3 trial without additional financing.
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129		-
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132	132	While the Phase 3 trial is being designed, Onconova Therapeutics has expanded the Phase 1/2 trial cohort by enrolling 45 additional patients. Under a protocol expansion, Onconova Therapeutics is using the expanded cohorts to explore dose optimization regarding efficacy and safety by increasing the dose of rigosertib oral to a total of 1120 mg in combination with full dose azacitidine and varying the dose administration scheme of rigosertib oral (560 mg before breakfast and 560 mg after lunch or 840 mg before breakfast and 280 mg after lunch) to identify an optimal dose and schedule. During this expansion, the company also instituted risk-mitigation strategies, as further described below, in order to address a urinary adverse event of interest, hematuria. After amendments were filed with the regulatory agencies, the company started the expansion phase of this trial in the U.S. sites that participated in the initial trial. Since the trial initiation, Onconova Therapeutics has added additional US sites to complete enrollment of the expanded trial. The first patient was enrolled in April 2017 and as of April 2018, complete enrollment of 45 patients was achieved in the expansion trial; and the trial is ongoing. Presentation of updated efficacy and safety data from rigosertib/azacitidine combination Phase 2 studies in MDS will be presented at the 60th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2018.
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135	135	In March 2018, at the 6th International Bone Marrow Failure Disease Symposium, the company presented data on the incidence of hematuria in 37 higher-risk MDS patients receiving rigosertib oral in combination with azacitidine as part of the Phase 1/2 expanded cohort. In the first part of the Phase 1/2 study, prior to the study expansion, of 42 patients studied with oral rigosertib 840 mg total and azacitidine, the incidence of hematuria was 48%. In 37 patients studied with oral rigosertib 1120 mg total and azacitidine in the Phase 1/2 expanded cohort, with the use of risk-mitigating strategies to minimize hematuria, the incidence of hematuria was 11% at the time of the presentation.  The study is ongoing and the company anticipate presenting updated data at the ASH Annual Meeting & Exposition in December 2018. The risk-mitigating strategies include the following:
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	135	+|2nd RIGO dose must be administered at 3 PM (±1 hour) at least 2 hours after lunch to minimize a nocturnal bladder dwell time| |Oral hydration of at least two liters of fluid per day is encouraged| |Recommended bladder emptying prior to bedtime| |Urine pH reading approximately 2 hrs after AM dose. Sodium bicarbonate suggested administration of 650 TID if pH tests < 7.5
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139		-<table here>
140		-
141		-
142	142	The comparison of the hematuria results from the two parts of this study are presented below:
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	139	+**Hematuria Comparison Between Rigosertib Combination Therapy Parts 1 and 2:**
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	141	+|All Patients on Combination Part 1 (Rigosertib 840 mg total & Azacitidine)| |42|
	142	+|Patients with hematuria| |20(48|)%
	143	+|Patients with grade 1 or 2 hematuria| |17(40|)%
	144	+|Patients with grade __>__3 hematuria| |5(12|)%
	145	+| | | |
	146	+|All Patients on Combination Part 2 (Rigosertib 1120 mg total & Azacitidine) with risk-mitigation strategies| |37|
	147	+|Patients with hematuria| |4(11|)%
	148	+|Patients with grade 1 or 2 hematuria| |4(11|)%
	149	+|Patients with grade __>__3 hematuria| |0(0|)%
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146		-
147		-Hematuria Comparison Between Rigosertib Combination Therapy Parts 1 and 2:
148		-
149		-
150		-
151		-<table here>
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153		-
154	154	In June 2017, at the Congress of the European Hematology Association Meeting, the company updated the data from the Phase 1/2 trial and highlighted results in AML patients included in this study. Response data was presented on eight evaluable patients with AML who were tested with the rigosertib and azacitidine combination. For the eight evaluable patients with AML, the combination was well tolerated and the safety profile was similar to single-agent azacitidine, based on safety information in the azacitidine FDA approved label. Based on the presented results of the combination studies, the authors concluded that continued study in AML was warranted. The company will not commence further development of rigosertib oral in combination with azacitidine for AML without additional financing.
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157	157	Upon completion of its Phase 1/2 study, the company will submit the study results to the applicable regulatory authorities.  The final results of this study may differ from the results presented above and the applicable regulatory authorities may not agree with its analyses. The combination trial with azacitidine is expected to advance to a pivotal Phase 3 trial for first-line higher-risk MDS patients in 2019, and the company will not commence the Phase 3 trial of oral rigosertib in combination with azacitidine for higher-risk MDS or AML without additional financing.
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	155	+//Rigosertib oral for lower-risk MDS//
159	159
160		-Rigosertib oral for lower-risk MDS
161		-
162		-
163	163	Onconova Therapeutics is also developing rigosertib oral as a single agent treatment for lower risk MDS. Higher-risk MDS patients suffer from a shortfall in normal circulating blood cells, or cytopenias, as well as elevated levels of cancer cells, or blasts in their bone marrow and sometimes in their peripheral blood with a significant rate of transformation to acute leukemia. Lower-risk MDS patients suffer mainly from cytopenias, that is low levels of red blood cells, white blood cells or platelets. Thus, lower-risk MDS patients depend on transfusions and growth factors or other therapies to improve their low blood counts; but have a lower rate of acute leukemic transformation.
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165		-
166	166	Onconova Therapeutics has explored single agent rigosertib oral as a treatment for lower-risk MDS in two Phase 2 clinical trials, 09-05 and 09-07. In December 2017, the company presented data at the Annual ASH Meeting from the 09-05 Phase 2 trial. This data demonstrated a 44% rate of achieving transfusion independence in the cohort of Lower -risk MDS patients treated with rigosertib oral at a dose of 560 mg BID (1120 mg over 24 hrs) two out of three weeks. To date, Phase 2 clinical data has indicated that further study of single agent rigosertib oral in transfusion-dependent, lower-risk MDS patients is warranted. Rigosertib has been generally well tolerated, except for urinary side effects at higher dose levels. Future clinical trials will be needed to evaluate dosing and schedule modifications and their impact on efficacy and safety results of rigosertib oral in lower-risk MDS patients.
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168		-
169	169	Data presented from the 09-05 trial also suggested the potential of a genomic methylation assessment of bone marrow cells to prospectively identify lower-risk MDS patients likely to respond to rigosertib oral. The company therefore expanded the 09-05 trial by adding an additional cohort of 20 patients to advance the development of this genomic methylation test. To date, a biomarker which would predict response has not been identified. Further testing and development of rigosertib oral for lower-risk MDS will be required. The company will not commence further development of rigosertib oral for lower-risk MDS without additional financing.
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	163	+//Safety and Tolerability of rigosertib oral in MDS and other hematologic malignancies//
171	171
172		-Safety and Tolerability of rigosertib oral in MDS and other hematologic malignancies
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174		-
175	175	As presented at the December 2016 ASH Annual Meeting, rigosertib oral as a monotherapy was evaluated in four Phase 1 and 2 studies in MDS and other hematologic malignancies. One study is completed and a clinical study report is available. The most common TEAEs in   > 10% of patients with MDS/AML (n=168) were pollakiuria (increased urinary frequency) (35%), fatigue (32%), diarrhea (26%), dysuria (29%) and haematuria (24%). The most common   > Grade 3 AEs were anaemia (17%), thrombocytopenia (5%), haematuria (4%) and urinary tract infection (4%). The most common serious AE was pneumonia (6%). The most common AEs leading to discontinuation of patients receiving rigosertib oral as monotherapy were dysuria (8%), urinary tract pain (7%), haematuria (5%) and urinary frequency (5%).
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178	178	In addition to the above described clinical trials, Onconova Therapeutics is continuing the preclinical and chemistry, manufacturing, and control work for IV and rigosertib oral.
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	169	+==== ====
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181		-Rare Disease Program in “RASopathies”
	171	+==== Rare Disease Program in “RASopathies” ====
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183		-
184	184	Based on the mechanism of action data published last year, Onconova Therapeutics has initiated a collaborative development program focusing on a group of rare diseases with a well-defined genetic basis in expression or defects involving the Ras Effector Pathways. Since “RASopathies” are rare diseases affecting young children, Onconova Therapeutics is embarking on a multifaceted collaborative program involving patient advocacy, government and academic organizations. The RASopathies are a group of rare diseases which share a well-defined genetic basis in expression or defects involving Ras Effector Pathways. They are usually caused by germline mutations in genes that alter the RAS subfamily and mitogen-activated protein kinases that control signal transduction and are among the most common genetic syndromes. Together, this group of diseases can impact more than 1 in 1000 individuals, according to RASopathiesNet.
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187	187	In January 2018, the company entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). Under the terms of the CRADA, the NCI will conduct research, including preclinical laboratory studies and a clinical trial, on rigosertib in pediatric cancer associated RASopathies.
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190	190	As part of the CRADA, the company will provide rigosertib supplies and initial funding towards non-clinical studies. The NCI will fund the majority of the research, including the cost of the clinical trial, which is expected to start in 2019. The NCI is carrying out PK/PD and dose escalation studies in preclinical models in preparation of dosing pediatric patients with single agent rigosertib. A clinical trial Phase 1 pediatric protocol has been developed and will be reviewed by the Institutional Review Board of the NCI. Based on NCI guidance, the company now expect the first patient to be treated in the first half of 2019.
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